Review

Leukemia (2008) 22, 686–707; doi:10.1038/leu.2008.26; published online 13 March 2008

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

L S Steelman1, S L Abrams1, J Whelan1, F E Bertrand1, D E Ludwig2, J Bäsecke3, M Libra4, F Stivala4, M Milella5, A Tafuri6, P Lunghi7, A Bonati7,8, A M Martelli9,10 and J A McCubrey1

  1. 1Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
  2. 2ImClone Systems, New York, NY, USA
  3. 3Division of Hematology and Oncology, Department of Medicine, Georg-August University, Göttingen, Germany
  4. 4Department of Biomedical Sciences, University of Catania, Catania, Italy
  5. 5Regina Elena Cancer Center, Rome, Italy
  6. 6Department of Cellular Biotechnology and Hematology, University La Sapienza of Rome, Rome, Italy
  7. 7Department of Clinical Sciences, University of Parma, Parma, Italy
  8. 8Unit of Hematology and Bone-Marrow Transplantation, University Hospital of Parma, Parma, Italy
  9. 9Department of Human Anatomical Sciences, University of Bologna, Bologna, Italy
  10. 10IGM-CNR, c/o IOR, Bologna, Italy

Correspondence: Dr JA McCubrey, Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, 600 Moye Boulevard, 5th Floor Brody Building 5N98C, Greenville, NC 27858, USA. E-mail: mccubreyj@ecu.edu

Received 28 November 2007; Revised 22 January 2008; Accepted 23 January 2008; Published online 13 March 2008.

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Abstract

Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia.

Keywords:

Raf, PI3K, Akt, signal transduction, inhibitors, chemotherapeutic drugs

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Introduction

In this first review, we summarize the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways with regard to how these cascades are regulated. We also discuss how these pathways can interact and cross-regulate each other. Furthermore, we discuss the effects of key mutations at critical components in these pathways and how they influence the leukemogenic process. In the accompanying review in this issue of Leukemia, we summarize how specific targeting of these pathways may enhance leukemia therapy.

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Overview of the Ras/Raf/MEK/ERK pathway

The Ras/Raf/MEK/ERK pathway is activated by many growth factors and cytokines that are important in driving proliferation and preventing apoptosis in hematopoietic cells.1, 2, 3, 4, 5 An overview of the effects of the Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways on downstream signaling pathways leading to growth and the prevention of apoptosis is presented in Figure 1. After receptor ligation, Shc, a Src homology (SH) 2 domain-containing protein, becomes associated with the C terminus of the growth factor receptor.6, 7, 8 Shc recruits the GTP-exchange complex growth factor receptor bound-2 (Grb2)/son of sevenless exchange (Sos) proteins (Grb2/Sos) resulting in the loading of membrane-bound Ras with GTP.9, 10 Ras:GTP then recruits Raf to the membrane where it becomes activated, likely via a Src family tyrosine (Y) kinase.11, 12, 13

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Overview of Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT Pathways. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are regulated by upstream growth factor receptors as well as various kinases. Many kinases serve to phosphorylate serine/threonine (S/T) and tyrosine (Y) residues on various proteins in this cascade. Some of these phosphorylation events serve to enhance activity (shown by a black P in a white circle) whereas others serve to inhibit activity (shown by a white P in a black circle. Phosphatases such as phosphatase and tensin homologue deleted on chromosome 10 (PTEN) that inhibit the function of proteins are indicated by a black octagon with white lettering. The downstream transcription factors regulated by these pathways are indicated in diamond-shaped outlines.

Full figure and legend (44K)

Raf is a multigene family that consists of RAF1, ARAF and BRAF, which encode proteins of 74, 68 and 94 kDa, respectively. The Raf proteins have three distinct functional domains: CR1, CR2 and CR3. The CR1 domain is necessary for Ras binding and subsequent activation. The CR2 domain is a regulatory domain. CR3 is the kinase domain. Deletion of the CR1 and CR2 domains produces a constitutively active Raf protein due to, in part, the removal of phosphorylation sites that serve to negatively regulate the kinase in the CR2 domain.14

Raf-1 is fairly ubiquitously expressed. B-Raf was originally thought to be expressed primarily in neuronal and hematopoietic tissues, but has since been shown to be expressed in more diverse tissues including melanocytes and thyroid cells that are hormonal responsive cell types. B-Raf mutations play significant roles in malignant transformation in melanocytes and thyroid cells as the hormones stimulate proliferation of B-Raf-dependent signaling pathways. A-Raf has a more limited tissue expression and is expressed in urogenital and intestine cells. A-Raf is expressed predominately in urogenital tissues, including the kidney.15 The different Raf genes have been knocked out in mice to examine some of the global roles of the Raf genes on development. ARAF deletion results in postnatal lethality attributed to neurological and gastrointestinal defects. BRAF deletion results in intrauterine death between days 10.5 and 12.5 and the mouse embryos display enlarged blood vessels and increased apoptosis of endothelial cells. Many of the functions of Raf-1 in RAF1 knockout mice are believed to be still present due to the presence of functional BRAF genes, and B-Raf can fulfill many of the functions of Raf-1.

Raf kinases are required for phosphorylation of the mitogen-associated/extracellular regulated kinase-1 (MEK1).16, 17, 18 MEK1 phosphorylates extracellular regulated kinases 1 and 2 (ERKs 1 and 2) on specific threonine (T) and Y residues.16, 17, 18 Activated ERK1 and ERK2 serine (S)/T kinases phosphorylate and activate a variety of substrates.19, 20, 21, 22, 23, 24, 25 90 kDa ribosomal six kinase 1 (p90Rsk1) is one such substrate. p90Rsk1 can activate the cyclic-AMP response element-binding protein (CREB) transcription factor.22 Moreover, ERK can translocate to the nucleus and phosphorylate additional transcription factors such as Elk1 and Fos that bind promoters of many genes, including growth factor and cytokine genes important in stimulating the growth and survival of hematopoietic cells.26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 The Raf/MEK/ERK pathway can also modulate the activity of many proteins involved in apoptosis including: B cell leukemia-2 (Bcl-2), Bad, Bim, myeloid cell leukemia-1 (Mcl-1), caspase 9 and survivin.38, 39, 40, 41, 42, 43, 44, 45, 46, 47

Raf-1 has many roles that are independent of MEK and ERK. It is important to discuss these interactions as they serve to illustrate the concept that targeting Raf, which will be covered in the accompanying review, will have additional effects than just inhibition of downstream MEK/ERK. Many of these non-MEK/ERK functions are involved in the prevention of apoptosis.4 Raf-1 interacts with mammalian sterile 20-like kinase (MST-2) and prevents its dimerization and activation.48, 49, 50 MST-2 is a kinase, which is activated by proapoptotic agents such as staurosporine and Fas ligand. Raf-1, but not B-Raf, binds MST-2. Depletion of MST-2 from Raf-1-/- cells abrogated sensitivity to apoptosis. Overexpression of MST-2 increased sensitivity to apoptosis. It was proposed that Raf-1 might control MST-2 by sequestering it into an inactive complex. This complex of Raf-1:MST-2 is independent of MEK and downstream ERK. Raf-1 can also interact with the apoptotic signal kinase (ASK1) to inhibit apoptosis.49 ASK1 is a general mediator of apoptosis and it is induced in response to a variety of cytotoxic stresses including tumor necrosis factor (TNF), Fas and reactive oxygen species (ROS). ASK1 appears to be involved in the activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs). These are examples of interactions of Raf-1 with kinases and antiapoptotic molecules that are independent of MEK and ERK. Raf-1 can also interact with Bcl-2 at the mitochondrion to influence its activity (Figure 1).

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Overview of the PI3K/PTEN/Akt/mTOR pathway

Growth factor/cytokine receptor ligation also leads to rapid activation of phosphatidylinositol 3-kinase (PI3K).51, 52 PI3K consists of an 85-kDa regulatory subunit, which contains SH2 and SH3 domains, and a 110-kDa catalytic subunit.51, 52 Cytokine stimulation often creates a PI3K-binding site on the cytokine receptor. The p85 subunit SH2 domain associates with this site.51, 52 The p85 subunit is then phosphorylated which leads to activation of the p110 catalytic subunit.

Class IA PI3Ks are heterodimeric proteins that consist of 85-kDa regulatory and 110-kDa catalytic subunits. An overview of the PI3K/PTEN/Akt/mTOR pathway is presented in Figure 1. The p85 regulatory subunit contains a SH2 domain, that recognizes phosphorylated Y residues, an inter SH2 domain (a rigid tether for p110), a conserved domain related to sequences present in the breakpoint cluster region (BCR) gene and a SH3 domain that are found in proteins that interact with other proteins and mediate assembly of specific protein complexes via binding to proline-rich motifs.53, 54 The 110-kDa PI3K class 1A catalytic subunit contains a p85-binding domain, a Ras-binding domain, a kinase domain and a helical domain.14, 52, 53, 54, 55 The p85 subunit SH2 domain associates with this site.50, 51, 55 The p85 subunit is then phosphorylated that leads to activation of the p110 catalytic subunit. This often occurs at the inner leaflet of the cytoplasmic membrane, although there are other important roles of PI3K in nuclear membranes that have been reviewed recently.56, 57, 58 A diagram illustrating some of the important roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in the cytoplasm and nucleus is presented in Figure 2. It is important to note that these two cascades, as well as the Jak/STAT pathway, also have critical features in the nucleus, although their initial activation often occurs by ligation of cytokine and other types of receptors expressed on the plasma membrane hematopoietic cells.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR have cytoplasmic as well as nuclear roles. Although the cytoplasmic membrane localized roles of these pathways are more frequently discussed, these pathways often have nuclear roles that are only beginning to be understood. Many of the nuclear functions of these pathways may regulate gene transcription, cell cycle progression as well as chromosome stability and replication. The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase is illustrated by a stop sign octagon as it has been shown to be an important tumor suppressor and have roles regulating apoptosis in the cytoplasm and cell cycle progression in the nucleus.

Full figure and legend (132K)

PI3K is a multigene family. There are at least eight distinct isoforms of the PI3K catalytic subunit and at least seven regulatory subunits.58 These genes encode proteins with different functions and there are probably many unknown functions that may play critical roles in activation/differentiation of hematopoietic cells which remain to be elucidated. PI3K lipid kinases have been grouped into three classes (I–III) according to their substrate preference and sequence homology.59, 60, 61, 62 The class I PI3K catalytic subunits have been grouped into two families, class IA and class IB. Class 1A consists of p110alpha (PIK3CA), p110beta (PIK3CB) and p110delta (PIK3CD). Class IA p110 are activated by tyrosine kinase receptors and Ras. Class IA p110 PI3Ks bind one of the three regulatory subunits p85alpha or the splice variants p55alpha or p50alpha that are encoded by PIK3R, p85beta encoded by PIK3R2 or p55gamma encoded by PIK3R3.

The p85alpha and p85beta proteins display a wide tissue distribution, while the p55gamma protein is more restricted and is highly expressed in brain and testis. The class IA regulatory subunits recruit the p110 catalytic subunit to phosphotyrosine (pY) residues in receptors, adapter proteins and other molecules. This localizes the class IA p110 subunits in the membranes where their lipid substrates reside. The adapter/regulatory subunits act to localize PI3K to the plasma membrane by the interaction of their SH2 domains with pY residues in activated receptors. They also serve to stabilize p110 and to limit its activity.

Class Ib p110 (p110gamma) is encoded by PIK3CG and is activated by G-protein-coupled receptors (GPCR) and Ras and binds the p101 regulatory molecule encoded by PIK3R5. The biological functions of the class IA PI3K regulatory and catalytic subunits are better described than the class Ib and classes 2 and 3 PI3K proteins. The rest of this review focuses on the class Ia PI3Ks and their downstream signaling partners. Although it should be realized that undoubtedly some of these other classes of PI3K proteins will be shown to have important roles in hematopoiesis and leukemia.

The class I PI3K-preferred substrate in vivo is phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) that is phosphorylated to yield phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 serves as an anchor for pleckstrin homology (PH) domain-containing proteins, such as Akt or phosphoinositide-dependent protein kinase-1 (PDK1). PtdIns(3,4,5)P3 is required for the membrane localization of Akt and PDK1.

PDK1 then phosphorylates Akt on a T regulatory residue. Akt is also a member of a multigene family (Akt-1, Akt-2 and Akt-3) and is also called protein kinase B (PKB) encoded by AKT1, AKT2 and AKT3, respectively. Depending on the Akt isoform, PDK1 can phosphorylate Akt on T308/309/305. A second kinase phosphorylates Akt on an S regulatory residue (S473/474/472).63, 64, 65, 66, 67 The identity of the second kinase (often referred to as PDK2) that phosphorylates Akt has remained elusive. Integrin linked kinase (ILK), PDK1, Rictor-mTOR complex (see below) and Akt autophosphorylation have all been suggested to be responsible for phosphorylation of Akt at the second S phosphorylation site.68 The PH domain leucine-rich repeat protein phosphatase (PHLPP) dephosphorylates S473 on Akt that induces apoptosis and inhibits tumor growth.69

Activated Akt is present both in the cytosol and the nucleus. In the cytosol, Akt-1 is functional when it is phosphorylated at T308 and S473 and translocated to the membrane via the PH domain and PtdIns(3,4,5)P3. Similar events are required for activation of Akt-2 and Akt-3. Nuclear Akt may play important antiapoptotic roles.56, 70 The differential biochemical contributions of Akt in the cytosol and the nucleus remain to be elucidated. Akt-1 and Akt-2 are fairly ubiquitously expressed. Akt-3 has a more limited tissue distribution and is expressed in the heart, kidney, brain, testes, lung and skeletal muscle.68 Akt has been postulated to phosphorylate over 9000 proteins.71, 72 Thus, Akt is clearly a critical growth regulatory switch.

Akt can transduce an antiapoptotic signal by phosphorylating downstream target proteins involved in the regulation of cell growth (for example, glycogen synthase kinase-3beta (GSK-3beta), ASK1, Bim, Bad, murine double minute-2 (MDM-2), p21Cip1 X-linked inhibitor of apoptosis (XIAP) and the Foxo3a transcription factor.63, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 Phosphorylated Foxo3a loses its ability to induce Fas, p27Kip1 Bim, Noxa and Puma gene transcription.84, 85

Akt also phosphorylates I-kappaB kinase (I-kappaK), which subsequently phosphorylates inhibitory subunit (I-kappaB) that binds nuclear transcription factor kappa light chain in B cells (NF-kappaB) transcription factor. When I-kappaB is phosphorylated it is ubiquitinated and subsequently degraded in proteosomes.86, 87, 88, 89, 90, 91, 92, 93 Disassociation of I-kappaB from NF-kappaB enables NF-kappaB to translocate into the nucleus to promote gene expression. The PI3K pathway can also phosphorylate and activate CREB that regulates transcription of antiapoptotic genes including Mcl-1, Bcl-2 and c-Jun.94, 95, 96 The PI3K pathway also results in activation of the mammalian target of rapamycin (mTOR) and ribosomal protein kinases such as p70 ribosomal six protein kinase (p70S6K)97, 98, 99, 100, 101, 102, 103, 104 these later two proteins play key roles in growth and size control. It is worth noting that Akt can cause the activation of specific substrates (for example, IkappaKalpha, CREB and MDM-2) or may mediate the inactivation of other proteins (for example, Raf-1, B-Raf (by the Akt-related kinase, serum glucocorticoid kinase (SGK)), p21Cip-1, Bim, Bad, procaspase-9, Foxo3a and GSK-3beta). This concept is important to remember as targeting Akt, which will be discussed in the accompanying review, may actually turn on (derepress) certain pathways (for example, Raf/MEK/ERK) which have pro-proliferative effects.

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Phosphatase regulation of the PI3K/PTEN/Akt/mTOR pathway

The PI3K pathway is negatively regulated by phosphatases. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is primarily a lipid phosphatase that removes the 3-phosphate from the PI3K lipid product PtdIns(3,4,5)P3 to produce PtdIns(4,5)P2 that prevents Akt activation.14, 55, 105, 106, 107, 108 PTEN is also a protein phosphatase.109, 110, 111 The ability of PTEN to function as a protein phosphatase remains controversial. PTEN has been proposed to dephosphorylate Fak and Shc that may alter cell motility.14 PTEN also has roles in both the nucleus and the cytoplasm. Some of these roles are illustrate in Figure 2. In the cytoplasm, PTEN is thought to have roles of suppressing apoptosis and regulating cell growth. In the nucleus PTEN has been postulated to function in regulating cell cycle progression, but it is also thought to have roles regulating cell growth by controlling p70S6K.

Two other phosphatases, SH2 domain-containing inositol 5'phosphatase 1 and 2 (SHIP-1 and -2), remove the 5-phosphate from PtdIns(3,4,5)P3 to produce PtdIns(3,4)P2.112, 113, 114, 115, 116 Mutations in these phosphatases as well as PTEN, which eliminate their activity, can lead to tumor progression. Consequently, the genes encoding these phosphatases are referred to as antioncogenes or tumor suppressor genes.

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Interactions of Akt with activator proteins

In a yeast two-hybrid search for proteins that interact with Akt and have roles in leukemia, the T-cell leukemia protein-1 (TCL1) was determined to bind Akt.117 TCL1 is a member of a multigene family that includes TCL1b and mature T-cell proliferation 1 (MTCP1). TCL1, TCL1b and MTCP1 were identified as translocated genes to the T-cell receptor (TcR) loci in chromosomal translocations present in human T-cell prolymphocytic and mature leukemia.118, 119, 120 These proteins contain 114, 106 and 128 amino acids, respectively. TCL1 is aberrantly expressed in many human diseases including Epstein–Barr Virus (EBV) transformed B-cell lymphoma, ataxia-telangiectasia, seminoma, dysgerminoma and AIDS-related lymphomas.68 TCL1 functions as an Akt coactivator and enhances its activity and nuclear translocation.121 TCL1 functions as a homodimer that is required for TCL1 to enhance Akt activation.122, 123, 124

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Effects of Akt on protein translation

Downstream of Akt are a complicated set of proteins critical for the regulation of cell growth that may also serve as targets for leukemia therapy. An overview of these downstream pathways and how they are regulated by both the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is presented in Figure 3. One key downstream protein of Akt is mTOR. mTOR is a 289-kDa S/T kinase. It regulates translation in response to nutrients/growth factors by phosphorylating components of the protein synthesis machinery, including p70S6K and eukaryotic initiation factor (eIF)-4E-binding protein (4EBP-1), the latter resulting in release of the translation initiation factor eIF-4E, allowing eIF-4E to participate in the assembly of a translational initiation complex.125 p70S6K, which can also be directly activated by PDK1, phosphorylates the 40S ribosomal protein, S6, leading to active translation of mRNAs.126 Integration of a variety of signals (mitogens, growth factors, hormones) by mTOR assures cell cycle entry only if nutrients and energy are sufficient for cell duplication.127, 128 Therefore, mTOR controls multiple steps involved in protein synthesis, but importantly enhances production of key molecules such as c-Myc, cyclin D1, p27Kip1 and retinoblastoma protein (pRb).129 mTOR also controls the translation of hypoxia-inducible transcription factor-1alpha (HIF-1alpha) mRNA. HIF-1alpha upregulation leads to increased expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).130 Moreover, HIF-1alpha regulates the glycolytic pathway by controlling the expression of glucose-sensing molecules including glucose transporter (Glut) 1 and Glut3.131

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Interactions between Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in protein translational control. The Raf/MEK/Erk and PI3K/PTEN/Akt/mTOR pathways both serve to regulate the activity of mTORC1 a protein complex consisting of MLST8, raptor and most importantly mammalian target of rapamycin (mTOR). This rapamycin-sensitive complex has both positive effects on mRNA translation growth, and cell size via regulating the activity of p70S6K and 4E-BP1. Furthermore, this complex can negatively regulate Akt activity. In contrast, the rapamycin-insensitive mTORC2 complex consisting of MLST8, SIN1, Raptor and mTOR phosphorylates and activates Akt.

Full figure and legend (40K)

By regulating protein synthesis, p70S6K and 4E-BP1 also control cell growth and hypertrophy, which are important processes for neoplastic progression resulting in leukemia. Akt-mediated regulation of mTOR activity is a complex multistep phenomenon. Akt inhibits tuberous sclerosis 2 (TSC2 or hamartin) function through direct phosphorylation.132 TSC2 is a GTPase-activating protein (GAP) that functions in association with the putative tuberous sclerosis 1 (TSC1 or tuberin) to inactivate the small G protein Rheb (Ras homologue enriched in brain).133 TSC2 phosphorylation by Akt represses GAP activity of the TSC1/TSC2 complex, allowing Rheb to accumulate in a GTP-bound state. Rheb-GTP then activates, through a mechanism not yet elucidated, the protein kinase activity of mTOR when complexed with the regulatory associated protein of mTOR (Raptor) adapter protein and mLST8, a member of the lethal-with-sec-thirteen gene family, first identified in yeast.72 The mTOR/Raptor/mLST8 complex (mTORC1) is sensitive to rapamycin and, importantly, inhibits Akt via a negative feedback loop that involves, at least in part, p70S6K, insulin receptor substrate-1 (IRS-1) and PI3K72 (Figure 3). The relationship between Akt and mTOR is further complicated by the existence of the mTOR/Rictor (rapamycin-insensitive companion of mTOR/mLST8 complex (mTORC2), which displays rapamycin-insensitive activity. The mTORC2 complex has been found to directly phosphorylate Akt on S473 in vitro and to facilitate T308 phosphorylation. Thus, the mTORC2 complex might be the elusive PDK2 that phosphorylates Akt on S473 in response to growth factor stimulation.134 Akt and mTOR are linked to each other via ill-defined positive and negative regulatory circuits, which restrain their simultaneous hyperactivation through a mechanism involving p70S6K and PI3K. Assuming that equilibrium exists between these two complexes, when the mTORC1 complex is formed, it could antagonize the formation of the mTORC2 complex and reduce Akt activity.134 Thus, at least in principle, inhibition of the mTORC1 complex could result in Akt hyperactivation. This is one complication with rapamycin treatment (see below) and the accompanying review.

Akt directly phosphorylates mTOR on S2448 that results in its activation.135 mTOR was found to be phosphorylated in acute myeloid leukemia (AML) blasts, along with its two downstream substrates, p70S6K and 4E-BB1, in a PI3K/Akt-dependent fashion.136, 137 Nevertheless, others failed to detect any relationship between PI3K/Akt signaling upregulation and p70S6K phosphorylation in AML primary cells.138 This might occur via the Raf/MEK/ERK pathway activating mTOR via ERK 1/2 phosphorylation.139 The Raf/MEK/ERK pathway is frequently activated in AML.140 Consistently, in some AML cases, treatment of blast cells with pharmacological inhibitors of ERK 1/2 signaling (U0126) suppressed p70S6K phosphorylation.137

GSK-3beta can negatively regulate mTOR by phosphorylating and activating TSC-2.141 These results further suggest GSK-3beta may be involved in the regulation of cell growth and malignant transformation. GSK-3beta activity seems also important for adhesion and Wnt-pathway beta-catenin expression and drug resistance in AML cells.142, 143 beta-Catenin expression in AML cells predicts enhanced clonogenic capacities and is associated with a poor prognosis.143 Thus, GSK-3beta also plays key roles in regulating proliferative loops involved in malignant transformation of hematopoietic cells.

A recently discovered proliferative loop in melanoma is controlled by c-Jun activity regulated by the CREB transcription factor that is activated by ERK and Akt.144 c-Jun can be inactivated by GSK-3beta. Elevated ERK leads to GSK-3beta phosphorylation and inactivation and results in a feed-forward loop which results in receptors for activated C kinase (RACK) transcription that acts in concert with protein kinase C (PKC) and MKK4/7 to regulate JNK and c-Jun phosphorylation and stability.144 When c-Jun is active it can induce the transcription of cyclin D1 that can affect hematopoietic cell proliferation and leukemia. The roles of this ERK-mediated inactivation of GSK-3beta in leukemia are not currently known, however, since activated ERK is detected frequently at elevated levels leukemia, there is a potential for this abnormal regulatory circuit playing a critical function in leukemogenic transformation.

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Overview of Jak/STAT pathway

The Jak/STAT pathway is another key signaling pathway activated after receptor ligation.1, 145 The Jak/STAT pathway consists of three families of genes: the JAK, or Janus family of tyrosine kinases, the signal transducers and activators of transcription (STAT) family and the suppressors of cytokine signaling/cytokine-induced SH2-containing (SOCS/CIS) family, which serves to downregulate the activity of the Jak/STAT pathway.1, 145 The Jak/STAT pathway involves signaling from the cytokine receptor to the nucleus. Jaks are stimulated by activation of a cytokine receptor. Stimulation of Jaks results in STAT transcription factor activity.

Jaks are a family of large tyrosine kinases, having molecular weights in the range of 120–140 kDa (1130–1142aa).145 Four Jaks (JAK1, JAK2, JAK3 and TYK2) have been identified in mammals. Jak proteins consist of seven different conserved domains (JH1–7). The JH1 constitutes a kinase domain, while JH2 is a pseudokinase domain. Many possible roles have been proposed for the different domains of the Jak proteins: (1) JH2 inhibits JH1, (2) JH2 promotes STAT binding, (3) JH2 is required for kinase activity of JH1 and (4) JH6 and JH7 are necessary for association of Jaks with cytokine receptors.145

Loss of Jak1 produces prenatal lethality due to neurological disorders,146 while Jak2-/- results in embryonic lethality due to defects in erythropoiesis.147, 148 Jak3 expression is limited to hematopoietic cells, and Jak3 knockout mice have developmental defects in lymphoid cells.147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160

Aggregation of cytokine receptors following activation allows formation of receptor homodimers and heterodimers. Receptor aggregation allows transphosphorylation of receptors and activation of the associated Jaks and STATs. Transphosphorylation occurs when one receptor kinase complex, in the absence of the ligand for the second receptor complex, phosphorylates and activates the second receptor complex. This may occur by interaction of functionally similar domains present on the two different signaling molecules. The best evidence of transphosphorylation is Jak1 mutant cell lines, which cannot activate Tyk2 after stimulation with interferon alpha/beta.145 Another example of this transphosphorylation is that interleukin-2 (IL-2) cannot activate Jak1 in the absence of Jak3.146, 161 Together these data indicate that receptor aggregation and transphosphorylation are important in activation of the Jaks.

The STAT gene family consists of seven proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) ranging in molecular weights from 73 to 95 kDa (748–851aa).145 The structure of the STAT family proteins consists of an N-terminal oligomerization domain, a DNA-binding domain in the central part of the protein, an SH2 domain and a transactivation domain near the C terminus. The transactivation domain is the most divergent in size and sequence and is responsible for activation of transcription. The oligomerization domain contains a tyrosine that is rapidly phosphorylated by Jaks, allowing the pY product to interact with the SH2 domains of other STAT proteins. Formation of STAT dimers promotes movement to the nucleus, DNA binding and activation of transcription, as well as increased protein stability. Threonine phosphorylation has been proposed to play a further role in the regulation of STAT activity.162, 163 This may be mediated by ERK,163 indicating a point of interaction between the Raf/MEK/ERK and Jak/STAT pathways (Figure 1).

The roles of the STAT and Jak proteins in hematopoietic growth have been investigated by the creation of knockout strains of mice.163, 164, 165, 166 STAT3-/- mice have severe developmental problems resulting in fetal death. Cytokine signaling abnormalities are associated with other STAT knockout models, but all mice are viable.

Constitutive STAT activity is associated with viral infections. STAT3 is known to have oncogenic properties.167, 168, 169, 170, 171 v-Abl and BCR-ABL induce constitutive STAT activity.167, 168 STAT transcription factors can induce antiapoptotic gene expression including Bcl-XL.

The Jak/STAT pathway is negatively regulated by the SOCS and CIS family of proteins.145 The more accepted name of this family is SOCS. This protein family consists of SOCS1–SOCS5 and CIS1.172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182 This family of genes has a conserved SH2 domain and SOCS box.172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182 The SOCS box, the C-terminal 40 amino acids, is implicated in stability and degradation of the protein by targeting it to the proteosome.175, 176, 177 CIS inhibits STAT5 activation by competing for its receptor-binding site.178, 179 SOCS2 directly binds and inhibits the kinase domain (JH1) of Jak2.179, 180, 181, 182 Gene ablation studies have indicated that the SOCS proteins have important roles in regulating the effects of interferon-gamma, growth hormone and erythropoietin. SOCS2 and SOCS3 knockout mice are lethal, whereas SOCS2 knockout mice are 30% larger than their wild-type counterparts.182, 183, 184, 185

There are other mechanisms to downregulate Jak/STAT signaling. Protein phosphatases, including CD45 and protein tyrosine phosphatase-alt epsilon C (PTPalt epsilonC), are also implicated in the negative regulation of Jak/STAT signaling.186, 187

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Interactions Between PI3K/PTEN/Akt/mTOR, Raf/MEK/ERK and Jak/STAT pathways that regulate apoptosis

Now that we have examined the basic mechanism of regulation of these pathways, we now discuss how these cascades interact to regulate apoptosis. When apoptosis is deregulated, which can occur by aberrant expression of these pathways, leukemia may arise. Akt can phosphorylate Raf-1 and B-Raf and leads to their inactivation.188, 189, 190, 191 Akt can also activate Raf-1 through a Ras-independent but PKC-dependent mechanism that results in the prevention of apoptosis.192 Suppression of apoptosis in some cells by Raf and MEK requires PI3K-dependent signals.193, 194, 195, 196, 197, 198 An overview of the effects of these pathways on the prevention of apoptosis is presented in Figure 4.

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Cytokines-mediated signal transduction pathways and prevention of apoptosis. Cytokines can induce multiple signal transduction pathways that can affect the expression of apoptotic molecules by transcriptional and posttranscriptional mechanisms.

Full figure and legend (84K)

The PI3K/PTEN/Akt/mTOR, Raf/MEK/ERK and Jak/STAT pathways contribute to the transcriptional regulation of Bcl-2 family members. Akt and Erk can regulate CREB phosphorylation. CREB binds the Mcl-1 and Bcl-2 promoter regions.96, 198, 199, 200 STAT can regulate Bcl-XL transcription. Moreover, the PI3K and Raf pathways phosphorylate proapoptotic Bcl2 homology-3 (BH3)-only domain protein Bad that prevents its apoptotic effects and it becomes cytoplasmically localized.201, 202, 203, 204 Another MAPK, JNK phosphorylates 14-3-3 proteins that results in their disassociation from cytoplasmically localized Bad. Bad then translocates to the mitochondrion.205 When Bad associates with Bcl-2 or Bcl-XL, it promotes apoptosis by preventing Bcl-2 or Bcl-XL from interacting with Bax.206, 207, 208, 209, 210, 211, 212 Bad is phosphorylated in most AML specimens suggesting that inhibition of Bad phosphorylation may be therapeutically important in AML.213 In contrast, the antiapoptotic Mcl-1 protein is not reported to interact with Bad.207 An overview of the effects of the PI3K/PTEN/Akt/mTOR and Raf/MEK/ERK pathways on Bad phosphorylation and the prevention of apoptosis is presented in Figure 5.

Figure 5.
Figure 5 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Overview of interactions between Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR, p53 and apoptotic pathways. All of these pathways interact to regulate the induction of apoptosis. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways normally serve to suppress apoptosis while p53, which is induced by certain chemotherapeutic drugs, will result in increases in proapoptotic family members and in some cases, growth factors such as hbEGF that may stimulate growth. Furthermore, p53 activity can be altered by phosphorylation by ERK as well as murine double minute-2 (MDM-2) levels, whose activity is in turn previously regulated by Akt. Hence these pathways are interconnected and serve to regulate each other. Not included in this diagram is the effect of c-Jun N-terminal kinase (JNK) that often is associated with proapoptotic effects and often serves to counterbalance the effects of extracellular regulated kinase (ERK) and Akt.

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Both the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways can phosphorylate the BH3-only domain protein Bim.42, 79 When Bim is phosphorylated by ERK and Akt, it is targeted for ubiquitination and degradation in the proteosome.46 Mcl-1 can bind Bim that prevents the activation and mitochondrial translocation of Bax.46, 47 In contrast, JNK can phosphorylate Bim at S65 that enhances its ability to induce Bax activation and hence stimulates apoptosis.208 Mcl-1 can also bind proapoptotic Bak.207 The Mcl-1:Bak interaction can be disrupted by the binding of the BH3-only domain Noxa protein that results in Mcl-1 being ubiquitinated and degraded in the proteosome.209 Bak can then form active dimers and induce apoptosis. Unlike Bcl-2 and Bcl-XL, the half-life of the Mcl-1 protein is short due to the N-terminal peptide sequence that is rich in proline (P), glutamic acid (E), serine (S) and threonine (T) (PEST sequence). Proteins containing PEST sequences are frequently targeted for proteosomal or calpain degradation.

The expression of Mcl-1 is regulated by both transcriptional and posttranslational mechanisms.214 Certain chemotherapeutic drugs such as taxol will induce Mcl-1 phosphorylation at different sites than those phosphorylated by ERK (T163).46 Oxidative stress can activate JNK that induces the phosphorylation of Mcl-1 on S121 and T163.215 Cytokine deprivation of certain hematopoietic cells induces GSK-3beta that in turn promotes the phosphorylation of Mcl-1 at S159 which results in its ubiquitination and degradation.216 Akt phosphorylates GSK-3beta suppressing its ability to phosphorylate Mcl-1. Altering the levels and phosphorylation state of Mcl-1 play important roles in the regulation of apoptosis.

The expression of BH3-only domain Puma and Noxa proteins are under the control of the PI3K/Akt pathway.217 Noxa interacts specifically with Mcl-1 but not with Bcl-2 or Bcl-XL.207 Bak associates with Mcl-1 and Bcl-XL but not Bcl-2. Upon induction of Puma and Noxa by p53 after genotoxic stress, Puma and Noxa displace Mcl-1 from Bak and Bak is able to oligomerize and induce apoptosis. This may lead to Mcl-1 degradation and apoptosis. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways increase Mcl-1 protein levels and stability. This may lead to an increase in Mcl-1 associated with Noxa and Puma and a decrease in free Bak levels and less apoptosis. A diagram depicting the effects of signaling and p53 pathways on Noxa and Puma and regulation of apoptosis is present in Figure 5.

Human caspase 9 was originally thought to be phosphorylated by Akt, but the murine caspase 9 lacks the Akt consensus phosphorylation site.18 Caspase 9 is phosphorylated by the Raf/MEK/ERK pathway at T125 that inhibits activation of the caspase cascade.19 Mcl-1 is a substrate for activated caspase 3, thus decreased caspase 9 activation by ERK phosphorylation will reduce caspase 3 activation and Mcl-1 cleavage and apoptosis will be suppressed.

Many cytokines and growth factors can also induce the Jak/STAT pathway that regulates the transcription of Bcl-XL.210 Bcl-XL can prevent the formation of Bax:Bax homodimers.212 Hence the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR, Jak/STAT and JNK pathways regulate many molecules involved in prevention of apoptosis. Dysregulation of these pathways may contribute to leukemia.

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Roles of the Ras/Raf/MEK/ERK pathway in leukemia

Now we discuss the roles that this cascade may play in leukemia. We also discuss some relevant examples of where altered expression of this pathway is important in the malignant transformation of other types of cancer (for example, solid tumors). It is important to discuss these other cancers as they provide us with information as to how aberrant expression of these pathways can cause cancer and alter the sensitivity of targeted therapy. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways can be activated by mutations/amplifications of upstream growth factor receptors. The FLT-3 kinase/growth factor receptor is mutated in greater than 25% of AMLs. The BCR-ABL chromosomal translocation is present in>95% of chronic myeloid leukemias (CMLs) and some acute lymphocytic leukemia (ALL) and can result in activation of these pathways. Other chromosomal translocations involving diverse genes are frequently present in AMLs. An illustration of some of the receptors, kinases and phosphatases mutated/amplified in leukemia that can result in activation of these pathways is presented in Figure 6.

Figure 6.
Figure 6 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Sites of mutation that can result in activation of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways in hematopoietic cells. Mutations have been detected in FLT-3, KIT, G-CSF, RAS and JAK. The BCR–ABL chromosomal translocation is present in virtually all chronic myeloid leukemias (CMLs) and some acute lymphocytic leukemias (ALLs). Many of these mutations and chromosomal translocations result in activation of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades. Although PI3KCA and BRAF are frequently mutated in certain solid tumors, it has not been documented to be frequently mutated in leukemia. The frequently mutated genes are indicated by a jagged symbol.

Full figure and legend (40K)

Mutations that lead to the expression of constitutively active Ras proteins have been observed in approximately 30% of human cancers.218, 219 These are often point mutations that alter key residues which affect Ras activity, although amplification of Ras is also detected in some tumors. Mutations that result in increased Ras activity also perturb the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades. BRAF has been reported to be mutated in approximately 7% of all cancers.220 However, this frequency may change as more and diverse tumors are examined for BRAF mutation. Recent studies indicated that mutated alleles of RAF1 and BRAF are present in therapy-induced acute myelogenous leukemia (t-AML).221 These leukemias arose after chemotherapeutic treatment of breast cancer patients. The mutated RAF1 genes detected were transmitted in the germ line, thus they are not spontaneous mutations in the leukemia but may be associated with the susceptibility to induction of t-AML in these Austrian cancer patients. Mutations of various genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway have been detected in therapy-related myelodysplasia and AML.222 In this study, the BRAF mutations were always associated to the translocation t(9;11)(p22;q23), involving the mixed lineage leukemia (MLL) gene.

For many years, the RAF oncogenes were not thought to be frequently mutated in human cancer and more attention to abnormal activation of this pathway was dedicated to RAS mutations that can regulate both the Raf/MEK/ERK and PI3K/PTENAkt/mTOR pathways. However, it was shown recently that BRAF is frequently mutated in melanoma (27–70%), papillary thyroid cancer (36–53%), colorectal cancer (5–22%) and ovarian cancer (30%).220, 223, 224 The reasons for mutation at BRAF and not RAF1 or ARAF in melanoma patients are not entirely clear. On the basis of mechanism of activation of BRAF, it may be easier to select for BRAF than either RAF1 or ARAF mutations. Due to the amino acids present in certain key regulatory sites in the different Raf isoforms, activation of B-Raf would require one genetic mutation whereas activation of either Raf-1 or A-Raf needs two genetic events. Furthermore, B-Raf may be activated in the cytoplasm by non-farnesylated Ras, while Raf-1 requires farnesylated Ras for translocation to the cell membrane.224

It was proposed recently that the structure of B-Raf, Raf-1 and A-Raf may dictate the ability of activating mutations to occur at these molecules, which can permit the selection of oncogenic forms.221, 224, 225 These predictions have arisen from determining the crystal structure of B-Raf.225 Like many enzymes, B-Raf is proposed to have small and large lobes, which are separated, by a catalytic cleft. The structural and catalytic domains of B-Raf and the importance of the size and positioning of the small lobe may be critical in its ability to be stabilized by certain activating mutations. In contrast, the precise substitutions in A-RAF and RAF-1 are not predicted to result in small lobe stabilization thus preventing the selection of mutations at ARAF and RAF1, which would result in activated oncogenes.225 Raf-1 has been known for years to interact with heat shock protein 90 (Hsp90). Hsp90 may stabilize activated Raf-1, B-Raf and A-Raf. The role that Hsp90 plays in selection of activated RAF mutations is highly speculative yet very intriguing.

The most common BRAF mutation is a change at nucleotide 600 that converts a valine to a glutamic acid (V600E) (V, valine; E, glutamic acid).220 This BRAF mutation accounts for over 90% of the BRAF mutations found in melanoma and thyroid cancer. It has been proposed that BRAF mutations may occur in certain cells, which express high levels of B-Raf due to hormonal stimulation. Certain hormonal signaling events will elevate intracellular cAMP levels, which result in B-Raf activation, leading to proliferation. Melanocytes and thyrocytes are two such cell types, which have elevated B-Raf expression as they are often stimulated by the appropriate hormones.226 Moreover, it is now thought that B-Raf is the most important kinase in the Raf/MEK/ERK cascade.220 In some models wild-type and mutant B-Raf activate Raf-1, which in turn activates MEK and ERK.220, 227, 228

In some cells, BRAF mutations are believed to be initiating events but not sufficient for full-blown neoplastic transformation.229, 230 Moreover, there appear to be cases where certain BRAF mutations (V600E) and RAS mutations are not permitted in the transformation process as they might result in hyperactivation of Raf/MEK/ERK signaling and expression, which may lead to cell cycle arrest.222 In contrast, there are other situations, which depend on the particular BRAF mutation and require both B-Raf and Ras mutations for transformation. The BRAF mutations in these cases are thought to result in lower levels of B-Raf activity.222, 230

Different BRAF mutations have been mapped to various regions of the B-Raf protein. Some of the other BRAF mutations are believed to result in B-Raf molecules with impaired B-Raf activity, which must signal through Raf-1.220, 228 Heterodimerization between B-Raf and Raf-1 may allow the impaired B-Raf to activate Raf-1. Other mutations, such as D593V, (D, aspartic acid) may activate alternative signal transduction pathways.220

It has been reported that a high frequency of AML and ALL (>50%) displays constitutive activation of the Raf/MEK/ERK pathway in absence of any obvious genetic mutation.140, 231 While there may be some unidentified mutation at one component of the pathway or a chromosomal translocation that feeds into the pathway or a phosphatase that regulates the activity of the pathway, the genetic nature of constitutive activation of the Raf/MEK/ERK pathway is unknown. Elevated expression of ERK in AMLs and ALLs is associated with a poor prognosis.232 Raf and potentially more effective MEK inhibitors may prove useful in the treatment of a large percentage of AMLs and ALLs. This will be addressed in an accompanying review in Leukemia.

Recently, it was demonstrated that there can be a genetic basis for the sensitivity of non-small cell lung cancers (NSCLC) to epidermal growth factor receptor (EGFR) inhibitors.233, 234, 235, 236, 237, 238 In addition, some melanoma cells carrying B-Raf mutations are sensitive to MEK inhibitors while cells lacking these B-Raf mutations are resistant.239 We have shown that introduction of activated EGFR mutants into hematopoietic cells renders them sensitive to EGFR inhibitors.233, 240, 241 Furthermore, introduction of activated Ras, Raf, MEK genes into hematopoietic cells makes them sensitive to MEK inhibitors.198, 242, 243, 244, 245 BCR-ABL-transformed hematopoietic cells are usually highly sensitive to inhibitors such as imatinib, providing that the particular BCR-ABL gene present in the cells does not have a mutation that eliminates sensitivity to the inhibitor.

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Roles of the PI3K/PTEN/Akt/mTOR Pathway in leukemia

Some Ras mutations can result in PI3K/PTEN/Akt/mTOR activation.246, 247, 248, 249, 250, 251 Mutations at the p85 subunit of PI3K have been detected in Hodgkin's lymphoma cells.252 The p110 subunit of PI3K is frequently mutated (approx25%) in breast and some other cancers but it not believed to be frequently mutated in leukemia.60, 253 Mutations and hemizygous deletions of PTEN have been frequently detected in AML and non-Hodgkin's Lymphoma (NHL).254, 255 PTEN inactivation is believed to occur frequently in certain hematopoietic neoplasms. Many different genetic mechanisms can result in functional inactivation or silencing of PTEN (see below).

A recent study observed that decreased PTEN phosphorylation was present in approximately 75% of AML patients.256 PTEN phosphorylation often results in inactivation of PTEN activity.256 PTEN phosphorylation was significantly associated with Akt phosphorylation and with shorter overall survival.256 Phosphorylation at the C-terminal regulatory domain of PTEN stabilizes the molecule, but renders it less active toward its substrate, PtdIns(3,4,5)P3.257 Moreover, PTEN expression has been shown to be low or absent in some AML patients,258 although the level of PTEN expression did not always correlate with the degree of Akt phosphorylation. However, a subsequent study failed to demonstrate that AML blasts have a decreased expression of PTEN.259 Another study of 62 AML patients, demonstrated that 15 of them had aberrant PTEN mRNA transcripts. However, all the samples with abnormal transcripts also displayed normal full-length transcripts, suggesting that the aberrant transcripts could have resulted from altered RNA splicing. Moreover, no loss of heterozygosity (LOH) or other types of genetic mutations were observed.260 PTEN-inactivating mutations do not appear to occur very frequently in AML.261, 262 Therefore, the importance, if any, of PTEN in causing Akt activation in AML blast cells remains unclear. Nevertheless, we feel that reinvestigation of the PTEN role in AML pathogenesis is necessary, since recent studies in mice demonstrated that bone marrow stem cells without functional PTEN multiplied rapidly, displayed diminished self-renewal capacity, migrated out of the bone marrow, colonized distant organs and initiated a leukemic-like disease.263, 264 Importantly, these effects were mostly mediated by mTOR, as rapamycin not only depleted leukemia-initiating cells, but also restored normal hematopoietic stem cell function.264

The NOTCH1 receptor, which is activated by mutations in at least 50% of T-cell acute lymphocyte leukemia (T-ALL), inhibits PTEN expression through the HES-1 transcription factor.265, 266 This in turn leads to Akt activation, and resistance to glucocorticoids. At some point during disease progression, the PTEN gene is either lost or inactivated through other genetic mechanisms (for example, gene hypermethylation), as even inhibition of NOTCH1 did not restore PTEN expression. Importantly, PTEN-null T-ALLs are resistant to NOTCH1 inhibitors (gamma-secretase inhibitors), however they are very sensitive to Akt inhibitors.256

More research has been done on PTEN mutations and gene silencing in solid tumors as opposed to hematopoietic cancers. Hence, we discuss what is known about PTEN mutation and regulation in breast cancer as some of these mechanisms that serve to silence this important tumor suppressor gene are likely to be present in hematopoietic neoplasias where PTEN is suppressed.

Germ-line PTEN mutation is present in approximately 80% of patients with Cowden syndrome (CS).53, 267 This disease, which is also known as multiple hamartoma syndrome, is a familial syndrome that includes many different types of cancer conditions including early onset breast cancer. Mutations have been reported to occur at PTEN in breast cancer in varying frequencies (5–21%).268, 269 LOH of PTEN is probably more common (30%) than deletion of both PTEN alleles. PTEN promoter methylation leads to low PTEN expression. In one study, 26% of primary breast cancers had low PTEN levels.269 Low PTEN levels have been correlated with lymph node metastases and poor prognoses.270 Mutations at certain residues of PTEN, which are associated with CS, affect the ubiquitination of PTEN and prevent nuclear translocation. These mutations leave the phosphatase activity intact.271 Inhibition of PTEN activity leads to centromere breakage and chromosome instability.272 PTEN expression may also be silenced in the absence of obvious genetic mutations. Disruption of PTEN activity by various genetic mechanisms could have vast effects on different processes affecting the sensitivity of leukemia to diverse therapeutic approaches. Thus, there are many possible mechanisms that can lead to elevated Akt levels which contribute to both leukemogenesis and lead to drug resistance. PTEN mutation/deletion/inactivation is present in many ALL lines. SHIP mutations are also detected in AML.273, 274 In summary, the PTEN and SHIP phosphatases play critical roles in leukemogenesis. We are only beginning to understand how these proteins function to regulate growth in normal hematopoietic stem cells and as we learn more about their pleiotropic effects, we may be able to understand their contributions to leukemic stem cells and be able to counteraffect the consequences of mutations that inactivate these proteins.

Increased Akt expression is linked with tumor progression and drug/hormonal resistance.275, 276, 277, 278, 279 Although PI3K and Akt have not been observed to be frequently mutated in the leukemia samples examined so far, we should be aware of studies that have been performed in solid tumors as this pathway is frequently activated in leukemia and in some cases associated with a poor prognosis. In a recent survey of 40 breast cancer lines, many were mutated at components of either the PI3K/PTEN/Akt/mTOR or Raf/MEK/ERK pathways;275 36% were mutated at PIK3CA (PI3K p110 subunit gene), 21% at PTEN (with either PTEN mutation or no protein present), 13% at KRAS, 5% at HRAS, 3% at NRAS and 10% at BRAF. In other studies it has been shown that the PIK3CA is mutated in approximately 25% of breast, 32% of colorectal, 27% of brain, 25% of gastric and 4% of lung cancers.279, 280, 281 These mutations frequently result in activation of its kinase activity. A recent report indicated that AKT1 is mutated in 8% of breast, 6% of colorectal and 2% of ovarian cancers examined.281 This mutation results in a lysine (K) substitution for E at amino-acid 17 (E17K) in the PH domain. Cells with this AKT1 mutation have not been observed to have mutations at PI3K; a similar scenario is also frequently observed with RAS and BRAF mutations.282 The AKT1 mutation alters the electrostatic interactions of AKT1 that allows it to form new hydrogen bonds with the natural phosphoinositol ligand.281 The PH domain mutation confers many different properties to the AKT1 gene. Namely, the mutant AKT1 gene (1) has an altered PH domain conformation, (2) is constitutively active, (3) has an altered cellular distribution as it is constitutively associated with the cell membrane, (4) morphologically transforms Rat-1 tissue culture cells and (5) interacts with c-Myc to induce leukemia in Emu-Myc mice (Emu, enhancer of immunoglobulin M (mu) gene; Myc, Myc oncogene originally isolated in avian myelocytomatosis virus).281 This PH domain-mutated AKT1 gene does not alter its sensitivity to ATP-competitive inhibitors, but does alter its sensitivity to allosteric kinase inhibitors.281 These results demonstrate that targeting the kinase domain of Akt may not be sufficient to suppress the activity of various AKT genes that have mutations in the PH domain.281 In a relatively small cohort of AML patients, such a mutation was not found.282 It will be important to determine if this AKT1 mutation (E17K) is also present in leukemias.

In summary, mutations do occur at key components of the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways in various cancers and targeting of these pathways may be important therapeutic approaches, either by themselves as monotherapy or by combination therapies with various chemo, hormonal and antibody treatments (see accompanying review).

The relationship between dysregulated PI3K activity and the onset of cancer is well documented. The PI3K is the predominant growth factor-activated pathway in LNCaP human prostate carcinoma cells.283, 284 Other reports directly implicate PI3K activity in a variety of human tumors including breast cancer,285 lung cancer,286 melanomas287 and leukemia288 among others. Activated Akt can affect the expression and regulation of the responses of hormone receptors and hence leads to ineffectiveness of hormone ablation therapies.288, 289, 290, 291

Activated Akt has been reported to be present in over 50% of primary AML samples and detection of activated Akt is associated with a poor prognosis.231 Furthermore, the Akt pathway has been shown to be involved in regulation of multidrug resistance protein-1 and drug resistance in AML and ALL.291, 292, 293, 294 Taken together, these data endorse the substantial role that PI3K signaling plays in oncogenesis and drug resistance. Moreover, targeted inhibition of the central components of this pathway appears to be an excellent choice for future therapeutic approaches. It has been observed that overexpression of both the Raf/MEK/ERK and PI3K/Akt pathways in AML is associated with a worse prognosis than overexpression of a single pathway.231 Thus, the development of inhibitors that target both pathways or the formulation of combinations of inhibitors may prove effective in leukemic therapy.

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Roles of the Jak/STAT pathway in neoplasia

A chromosomal translocation forming the TEL–Jak2 fusion protein that results in constitutive kinase activity has been observed in a limited number of patients with ALL and CML.295 This chimeric protein abrogates the cytokine dependence of certain hematopoietic cell lines. On the other hand, the partner TEL gene (translocated ETS in leukemia) is often rearranged in human leukemia. TEL rearrangement partners include Abl, platelet-derived growth factor receptor (PDGF-R) and Jak, all of which encode tyrosine kinases.296 The fusion products encode constitutively active tyrosine kinases involved in human leukemia. Activation of Jak in TEL–Jak is due to the oligomerization domain provided by the TEL transcription factor that results in the constitutive, ligand-independent activation of the Jak kinase domain. Activated Jak proteins have been made from the TEL–Jak rearranged chromosomal translocation. A summary of common chromosomal translocations in leukemia and some of the known signaling pathways activated by these translocations is presented in Tables 1 and 2.297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335 Recently, it has been discovered that the Jak2 kinase is frequently mutated in myeloproliferative diseases.336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372



STAT overexpression is frequently observed in human cancers. Increased STAT activation may contribute to the myeloproliferative diseases that harbor the Jak2 mutation. The STAT3 protein can function as an oncogene and other STAT proteins may function in oncogenic transformation. The STAT molecules provide novel therapeutic targets for oncogenic transformation. Activating mutants of STAT5a have been made, which will abrogate the cytokine dependence of hematopoietic cells.

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Conclusions

Over the past 25 years, there has been much progress in elucidating the involvement of the Ras/Raf/MEK/ERK, PI3K/PTEN/Akt and Jak/STAT cascades in promoting normal cell growth, regulating apoptosis as well as the etiology of human neoplasia and the induction of chemotherapeutic drug resistance. From initial seminal studies that elucidated the oncogenes present in avian and murine oncogenes, we learned that ERBB, RAS, SRC, ABL, RAF, PI3K, AKT, JUN, FOS, ETS and NF-kappaB (Rel) were originally cellular genes which were captured by retroviruses. Biochemical studies continue to elucidate the roles that these cellular and viral oncogenes have in cellular transformation. We have learned that many of these oncogenes are connected to the Ras/Raf/MEK/ERK, PI3K/PTEN/PDK/Akt and Jak/STAT pathways and either feed into this pathway (for example, BCR–ABL, ERBB) or are downstream targets, which regulate gene expression (for example, JUN, FOS, ETS and NF-kappaB). Furthermore, many of these 'oncogenes' are also present in chromosomal translocations that play key roles in leukemia (BCR–ABL, TEL–JAK, TEL–PDGFR).

The Ras/Raf/MEK/ERK pathway has what often appears to be conflicting roles in cellular proliferation, differentiation and the prevention of apoptosis. Classical studies have indicated that Ras/Raf/MEK/ERK can promote proliferation and malignant transformation in part due to the stimulation of cell growth and at the same time results in the prevention of apoptosis. Furthermore, an often overlooked aspect of Raf/MEK/ERK cascade is its effects on cytokine and growth factor gene transcription that can stimulate proliferation. The latest 'hot' area of the Raf/MEK/ERK pathway is the discovery of BRAF gene mutations in human cancer, which can promote proliferation and transformation.218 However, it should be remembered that only a few years ago, hyperactivation of B-Raf and Raf-1 was proposed to promote cell cycle arrest.4 Thus, it is probably fine-tuning of these mutations, which dictates whether there is cell cycle arrest or malignant transformation.

Initially it was thought that Raf-1 was the most important Raf isoform. RAF1 was the earliest identified RAF isoform and homologous genes are present in both murine and avian-transforming retroviruses. Originally it was shown that Raf-1 was ubiquitously expressed, indicating a more general and important role while B-Raf and A-Raf had more limited patterns of expression. However, it is now believed that B-Raf is the more important activator of the Raf/MEK/ERK cascade and in some cases, activation of Raf-1 may require B-Raf. However, Raf-1 rears its head again in the cancer field by the recent discovery that there are mutant RAF-1 alleles in certain therapy-induced t-AMLs that are transmitted in a Mendelian fashion.221 The role of A-Raf remains poorly defined yet it is an interesting isoform. It is the weakest Raf kinase, yet it can stimulate cell cycle progression and proliferation without having the negative effects on cell proliferation that B-Raf and Raf-1 can exert.243

Activation of the Raf proteins is very complex as there are many phosphorylation sites on Raf. Phosphorylation at different sites can lead to either activation or inactivation. It is important for the clinician and basic scientist to have a general understanding of the complexity of protein phosphorylation. Targeting a kinase will not necessarily be a simple thing. Inhibition of one kinase might result in activation of another kinase cascade that may have pro-proliferative effects. Clearly, there are many kinases and phosphatases that regulate Raf activity and the phosphorylation will determine whether Raf is active or inactive. While the kinases involved in regulation in Raf/MEK/ERK have been extensively studied, there is only very limited knowledge of the specific phosphatases involved in these regulatory events.

Raf-1 has many roles, which are apparently independent of downstream MEK/ERK. Some of these functions occur at the mitochondria and are intimately associated with the prevention of apoptosis. Raf-1 may function as a scaffolding molecule to inhibit the activity of kinases that promote apoptosis.

The Raf/MEK/ERK pathway is both positively (Hsp90, kinase suppressor of Ras (KSR), MEK partner-1 (MP-1)) and negatively (Raf kinase inhibitory protein, RKIP, 14-3-3) regulated by association with scaffolding proteins. The expression of some of the scaffolding proteins is altered in human cancer (for example, RKIP) in some cases. Some of these scaffolding proteins (for example, Hsp90) are being evaluated as potential therapeutic targets (Hsp90 is a target of geldanamycin, modified geldanamycins are in clinical trials). Potential roles of Hsp90 in stabilizing activated forms of Raf are intriguing and may allow the evolution of activated mutant forms of Raf.

The Raf/MEK/ERK pathway is intimately linked with the PI3K/PTEN/Akt/mTOR pathway and they interact to regulate cell growth, apoptosis and malignant transformation. Ras can regulate both pathways. Furthermore, in some cell types, Raf activity is negatively regulated by Akt indicating a cross talk between the two pathways. Both pathways may result in the phosphorylation of many downstream targets and impose a role in the regulation of cell survival and proliferation. These pathways phosphorylate many key proteins involved in apoptosis (Bad, Bim, Mcl-1, caspase 9, Ask-1 and others), which serve to alter their activities and subcellular localization. The phosphorylation events mediated by Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are associated with the prevention of apoptosis. In contrast, another MAPK, JNK also phosphorylates many of these molecules, and these phosphorylation events often have opposite effects as those elicited by the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Interestingly, Ras and Raf mutations may not always result in similar outcomes. For example a Ras mutation would be predicted to activate both the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Activation of PI3K/PTEN/Akt/mTOR could result in the suppression of Raf/MEK/ERK. However, mutation at either B-Raf or Raf-1 would result in only activation of Raf/MEK/ERK.

Although we often think of phosphorylation of these molecules as being associated with the prevention of apoptosis and the induction of gene transcription, this view is oversimplified. For example, in certain situations such as those leukemias that have a deleted/silenced PTEN gene, the Raf/MEK/ERK pathway may be inhibited; hence the phosphorylation of Bad and CREB normally mediated by the Raf/MEK/ERK cascade, which is associated with the prevention of apoptosis, will be inhibited. Likewise it is important to remember that phosphorylation at certain protein residues may result in enhanced activity whereas phosphorylation at different residues could result in decreased activity. For example, phosphorylation of Bim by JNK is linked with the promotion of apoptosis while phosphorylation of Bim by Raf/MEK/ERK or PI3K/Akt pathways is associated with the prevention of apoptosis.

Although it has been known for many years that the Raf/MEK/ERK pathway can effect cell cycle arrest, differentiation and senescence, these are probably some of the least studied research areas in the field due to the often cell lineage-specific effects that must be evaluated in each cell type. An intriguing aspect of leukemia therapy is that in some cases stimulation of the Raf/MEK/ERK pathway may be desired to promote terminal differentiation, while in other types of malignant cancer cells that proliferate in response to Raf/MEK/ERK activity, inhibition of the Raf/MEK/ERK pathway may be desired to suppress proliferation. Thus, we must be flexible in dealing with the Raf/MEK/ERK pathway. As we learn more, our conceptions continue to change.

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References

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Acknowledgements

JAM and LSS have been supported in part by a grant from the NIH (R01098195). JB was supported in part by the Deutsche Krebshilfe. AB, PL and AT have been supported in part from grants from Associazione Italiana Ricerca sul Cancro (AIRC). AMM has been supported in part by grants from the CARISBO Foundation and the Progetti Strategici Università di Bologna EF2006.