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March 2001, Volume 15, Number 3, Pages 313-331
Table of contents    Previous  Article  Next   [PDF]
Transcription factors and translocations in lymphoid and myeloid leukemia
H N Crans and K M Sakamoto

Division of Hematology-Oncology, A2-412 MDCC, Departments of Pediatrics, and Pathology and Laboratory Medicine, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

Correspondence to: K M Sakamoto, 10833 Le Conte Ave., A2-412 MDCC, Los Angeles, California 90095-1725, USA; Fax: 310 206 8089


Chromosomal translocations involving transcription factors and aberrant expression of transcription factors are frequently associated with leukemogenesis. Transcription factors are essential in maintaining the regulation of cell growth, development, and differentiation in the hematopoietic system. Alterations in the mechanisms that normally control these functions can lead to hematological malignancies. Further characterization of the molecular biology of leukemia will enhance our ability to develop disease-specific treatment strategies, and to develop effective methods of diagnosis and prognosis. Leukemia (2001) 15, 313-331.


transcription factor; translocation; leukemia


The balance between the production and destruction of elements found in the blood must be tightly controlled, yet flexible enough to maintain homeostasis. It is essential in the cell cycle to maintain an appropriate balance between proliferation and quiescence or differentiation.

Leukemia is defined as the abnormal, uncontrolled proliferation of one or more cells of the hematopoietic lineage. Leukemias result from the accumulation of mutations in genes such as oncogenes and/or tumor suppressor genes, and the loss of coordination between proliferation and differentiation in the hematopoietic progenitor cell pool. Chromosomal translocations, resulting in chimeric genes which alter the normal properties of the resulting protein, are another type of chromosomal abnormality that can contribute to oncogenic change in cells. The regulation of both the proliferation and differentiation of hematopoietic cells is essential in leukemogenesis.1

The different types of leukemia are classified according to duration of the disease, number of white blood cells present in the peripheral blood, and the type of white blood cell involved. In acute leukemia, there is a predominance of immature cell types, blasts and 'pro' stages, and in chronic leukemia the cell types are predominately mature.1

Chromosomal abnormalities have been found in more that 60% of patients with acute myelogenous leukemia (AML) and 65% of those with acute lymphoblastic leukemia (ALL).1 Leukemia can occur at any age, however chronic lymphocytic leukemia (CLL) is usually found in persons over 50 years of age, whereas acute leukemias are generally found in persons under 20 years of age.1

Transcription factors

The transcription of the DNA of a gene into messenger RNA takes place in the nucleus and is the first step in protein synthesis. Located in the nucleus, transcription factors regulate the transcription of target genes. They bind to target DNA sequences and regulate functions such as cell growth, development, and differentiation. The transcribing machinery is a complex of many proteins, some in common for all genes and some unique to particular gene targets.2 To aid RNA polymerase in recognizing their promoters on DNA molecules, one or more sequence-specific DNA-binding proteins must be bound to the DNA to form a functional promoter. These transcription factors are necessary for the initiation of RNA synthesis.3

Transcription is regulated in part by HAT enzymes (histone acetyltransferase) which add acetyl groups to the amino acid lysine in histones.2 The acetylation and deacetylation of histones are thought to be the key machinery of transcriptional activation and repression.4 Histone acetylation weakens the interaction of histones with DNA and induces alterations in nucleosome structure. This enhances the accessibility of targeted promoters to components of the transcription machinery, thereby increasing transcription.5,6 This also plays an important role in some types of cancer-specific therapies, such as treatment of acute promyelocytic leukemia with all-trans retinoic acid (ATRA). This works in part by inducing the dissociation of transcriptional co-repressors from the fusion protein PML/RARalpha and thereby releasing suppression of Sin3 and histone deacetylase from the transcriptional complex, allowing the cells to differentiate.7 Another way in which transcriptional activation can be regulated is through ubiquitin-dependent proteolysis.8

Hematopoiesis and transcription factors

Hematopoiesis is defined as blood cell development from pluripotent hematopoietic stem cells to at least eight phenotypically distinct mature blood cell lineages (Figure 1).9 In order to ensure that each resulting cell type expresses the genes necessary for its function, transcription factors must be able to be employed in both general and restricted expression patterns. In this way, they enable hematopoietic cells to attain functionally distinct phenotypes through the activation of specific gene expression and thus, control much of hematopoiesis.

Oncogenic activity can result from the activation of existing transcription factors, abnormal expression of transcription factor genes, or the formation of chimeric transcription factor genes. These oncogene products, which can also include growth factors, kinases, and GTP-binding proteins, as well as transcription factors, participate in the signaling pathways from the cellular surface to the nucleus. Processes such as stem cell self-renewal or commitment to differentiation and progenitor cell expansion or terminal differentiation are controlled by the activity of growth factors and nuclear regulators. Alterations in any part of the signaling pathways, such as chromosomal abnormalities, have the potential to induce transformation.

The formation of chimeric transcription factor proteins can alter the expression of cellular genes and lead to oncogenic activity. Through their association with chromosomal translocations and a particular morphogenic or phenotypic type of leukemia, it has been shown that transcription factors are common targets that may be involved in leukemogenesis. Cloning the genes at the breakpoints of these rearrangements has had a valuable impact on our understanding of the molecular biology of cancer. In this paper, we will discuss examples of transcription factors involved in specific types of leukemia, which are listed in Table 1.

Acute myeloid leukemia


The Wilms' tumor suppressor gene (WT1) encodes a zinc finger transcription factor involved in tissue development, in cell proliferation and differentiation, and in apoptosis.10 Wilms' tumor, a nephroblastoma, is a pediatric malignancy of renal blastemal cells. The WT1 gene has been classified as a tumor suppressor gene,10 as well as an oncogene.11 The WT1 gene product acts as a regulator of gene expression depending on how it combines with other regulatory proteins in different cell types.11 It contains a proline-rich amino terminus which functions as a transcriptional repressor12 and four contiguous cys2-his2 zinc fingers at the carboxy end, which bind DNA in vitro.13,14 It is mapped to chromosome 11p13 and is encoded by 10 exons.15

The Wilms' tumor gene is expressed in fetal spleen, bone marrow, and immature leukemic cells15,16,17,18,19 and the down-regulation is thought to be required for differentiation of some hematopoietic lineages.20,21 Expression is decreased in differentiated leukemia cells both in vivo and in vitro and is upregulated in fetal spleen and immature leukemia cells.22 Additionally, WT1 exhibits oncogenic potential in specific cellular contexts through the transcriptional upregulation of anti-apoptotic genes such as bcl-2.23

The WT1 protein plays an essential role in the growth of leukemic and solid tumor cells. Elevated expression of the wild-type WT1 gene has been identified in almost all leukemic cells, independent of the type of disease.11,24 In leukemic cells, the WT1 gene has been shown to function as an oncogene.11,25,26,27 The WT1 wild-type expression level in cells shows an inverse correlation between WT1 expression levels and prognosis.24 There is an increased WT1 expression at relapse compared with that at diagnosis in cases of acute leukemia,11 as well as growth inhibition of leukemic cells which occurs with WT1 antisense oligomers.25 Furthermore, in the 32D cl3 myeloid progenitor cell line and in normal myeloid progenitor cells, a block in differentiation and an induction of proliferation in response to G-CSF was seen.26,27

Evidence suggests that the critical transformation events in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) occur in immature CD34+ progenitor cells.28 In immuno-compromised murine recipients transplanted with purified cells from patients with AML, only immature CD34+ cells were capable of initiating leukemia.29 In addition, purified CD34+ cells from patients with CML efficiently initiated leukemia in murine recipients.30,31 WT1 is expressed in immature CD34+ progenitor cells, and as mentioned earlier, its down-regulation is associated with differentiation.32 Elevated levels of WT1 have been seen in purified CD34+ cells from patients with AML and CML24,33 and increased WT1 expression has been shown to block normal differentiation and enhance proliferation of hematopoietic progenitor cells. These findings can help to explain the potential role of WT1 in the leukemic process.26,28,34


The AML1 gene, on chromosome 21q22, is one of the most frequently mutated genes associated with human acute leukemia and forms the fusion proteins AML1/ETO (Figure 2a) and AML1/MDS/EV1 in AML, and TEL/AML1 in B-lineage acute lymphocytic leukemia.35

Core binding factor alpha2 (CBFalpha2 or AML1) is a DNA-binding subunit in the family of core binding factors (CBFs). CBF is a family of heterodimeric transcription factors that contain a common CBFbeta subunit bound to one of three CBFalpha subunits.36 Expressed in hematopoietic cells, it is a key regulator of early hematopoiesis. AML1 and other CBFalpha proteins have recognition sequences that are required for tissue-specific expression of several hematopoietic genes. These include macrophage colony-stimulating factor (M-CSF) receptor, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), T cell receptors, immunoglobin M heavy chain, defensin NP-3, myeloperoxidase, and bcl-2.37,38,39,40,41,42,43,44,45 Homozygous disruptions in AML1 or CBFalpha result in a complete block in fetal liver hematopoiesis resulting in embryonic lethality, demonstrating the important role of the transcription factor complex in normal definitive hematopoiesis.46,47,48,49,50

The AML1 gene alpha subunit has a DNA-binding domain located near its N-terminus which is homologous to the product of Drosophila segmentation gene Runt; a 128 amino acid domain that is also responsible for heterodimerization.51 AML1 forms a heterodimer between the DNA binding alpha subunit and the beta subunit, CBFbeta, which does not bind DNA directly, but enhances the binding of the alpha subunit.52,53 It has been shown to be important in transcriptional activation and repression and it has also been implicated in DNA replication, although evidence suggests that the critical target genes have yet to be identified.54

The ETO gene is located on chromosome 8q22 and encodes the mammalian homologue of the Drosophila protein Nervy.55 Identification of other ETO family members involved in translocations with AML1 suggests that ETO sequences are critical for the transforming activity of these fusion proteins.54 Experimental evidence involving interactions between ETO and the nuclear co-repressors N-CoR and Sin3A, which can recruit an active histone deacetylase, suggests that it is likely to function as a regulator of transcription.56,57,58 ETO can form homodimers and heterodimers and it is likely that these multi-subunit complexes function in transcriptional regulation and the formation of different heterodimers may lead to functional differences in the activity of these complexes.54

The first genetic rearrangement to be discovered was t(8;21) in patients with a form of acute myelogenous leukemia (AML).59 The AML1 gene is located at the translocation breakpoint on chromosome 21 in the t(8;21)(q22;q22) translocation (AML1/ETO)60 and the fusion protein is present in 12% of AML cases.35 The encoded fusion protein consists of the N-terminal 177 amino acids of AML1 fused in-frame to almost the complete ETO protein.54 It is still able to heterodimerize with CBFbeta and interact with CBF DNA-binding sites, however the fusion protein binds through its ETO sequences to both ETO/MTG family members and a co-repressor complex which results in repression of genes that are normally activated by AML/CBFbeta, thereby inhibiting transcription.38 AML1/ETO also activates the promoters of the genes encoding bcl-2 and the M-CSF receptor through AML1-binding sites and is expressed in myeloid progenitor cells.61,62

The ectopic expression of the AML1/ETO fusion gene product in 32Dcl3 murine myeloid precursor cells has been shown to stimulate cell proliferation without inducing morphologic terminal differentiation into mature granulocytes in response to G-CSF.43,63,64 In addition, AML1/ETO gene expression has also been found to elevate the expression of the G-CSF receptor.65 This upregulation depends on the CCAAT/enhancer binding protein (C/EBP) binding site, which suggests that the overproduction of G-CSF receptor is at least partly mediated by C/EBPepsilon, whose expression is activated by AML1/ETO.65 High expression of G-CSF receptor was also found in leukemic cells of patients with t(8;21), implying that G-CSF-dependent cell proliferation of myeloid precursor cells may play a role in the leukemic process.65


The Myb transcription factors are essential regulators of tissue-specific gene expression in the hematopoietic system. The product of the cellular myb, c-myb, gene is a highly conserved transcription factor of 75 kDa10,66,67 that has been shown to be required for definitive hematopoiesis.68 The c-Myb protein contains three different domains: a DNA-binding domain, a trans-activating domain, and a negative regulatory domain.69 C-myb was identified as an oncogene after transduction into the avian retroviruses, avian myeloblastosis virus and E26, which cause acute myeloblastic leukemia or erythroblastosis.70,71 In addition, c-myb has been identified as a target of retroviral insertional mutagenesis, resulting in T and B cell lymphomas in chickens and myeloid leukemia in mice.72,73,74,75,76,77,78

C-myb exerts its hematopoiesis-specific function through its DNA binding-dependent transactivating activity. This was shown through the identification of genes expressed during the early stages of hematopoiesis, regulated by a c-myb-induced cascade in a hematopoiesis-specific program.68 Expression of c-Myb is abundant within immature hematopoietic cells of all lineages79,80 and is downregulated during terminal differentiation.81,82,83

The functions of c-Myb include apoptosis, differentiation, and proliferation.84,85 Using dominant negative c-Myb targeted to T cells in transgenic mice, its tissue specific function was inactivated. Thymocytes from these mice underwent apoptosis at a higher rate than normal. The anti-apoptotic role of c-Myb in both T cells and myeloid cells is associated with Myb's ability to regulate expression of bcl-2.86,87,88 C-Myb's role in differentiation was demonstrated through the identification of markers of mature myeloid cells as target genes of c-Myb.89 Furthermore, the homeobox gene GBX2, another c-Myb target gene, plays a role in lineage commitment in differentiation90 and forced expression of c-myb in vitro inhibits erythroid differentiation.91 Myb's oncogenic characterization is thought to be due in part to the involvement in proliferation.89 The expression of c-Myb is closely linked to proliferative status in normal hematopoiesis. Following terminal differentiation to monocytes, neutrophils, or erythrocytes, c-Myb is downregulated.81,92 Genes implicated as targets of c-Myb which are involved in its role in proliferation include the cell cycle regulator gene Cdc2,90 the DNA polymerase alpha gene,93 c-kit94,95,96 and c-myc,97,98,99 however recent studies question the regulation of c-myc by c-Myb.89 In addition, antisense oligonucleotides to c-myb inhibit myeloid cell proliferation100 and overexpression of c-Myb is known to inhibit cellular differentiation in erythroid and myeloid cell lines.101,102

Acute myeloid leukemia is associated with high levels of c-myb expression and it has been suggested that c-myb plays a role in leukemogenesis.103,104 C-Myb can directly transactivate the promoter of cyclin A1, and it is thought that c-Myb might be involved in the high expression of cyclin A1 observed in AML. This suggests that c-Myb induces hematopoiesis-specific mechanisms of cell cycle regulation.104 The reason for the high level of cyclin A1 is unknown, but very high levels have been found in leukemic cell lines and leukemic blast cells from the majority of patients with AML.104

During hematopoiesis, c-myb is expressed during the stages of differentiation associated with high cellular proliferation and may act in part by driving expression of genes involved in regulation of the cell cycle.104 Additionally, the initiation of the leukemic phenotype is usually associated with inappropriate expression of c-myb,89 however, further investigation is necessary to determine the specific target genes of c-myb involved in leukemogenesis.


The human ELL gene, on chromosome 19p13.1, was originally identified as a gene that undergoes frequent translocations with the trithorax-like MLL gene on chromosome 11q23 in AML, resulting in the t(11;19)(q23;p13.1) chromosomal translocation.105,106 The regulation of transcriptional elongation by RNA polymerase II has become the focus of some studies as a result of discoveries that loss of regulation of transcription is associated with a variety of human diseases.107 ELL is thought to play a role in the regulation of gene expression and in the development of leukemia due to its function in encoding an RNA polymerase elongation factor.107

ELL is a 621-amino acid,107 80-kDa RNA polymerase II (Pol II) elongation factor that increases the overall rate of transcription elongation by RNA polymerase II, via suppression of transient pausing by the polymerase at many sites along DNA.108,109 ELL can increase the catalytic rate of transcription elongation by Pol II from both promoter-independent and promoter-dependent templates.108,110,111,112 It contains a novel type of Pol II interaction domain that can repress polymerase activity in promoter-specific transcription in vitro.110,113 The ELL protein can regulate both the transcriptional initiation and elongation activities of Pol II.109 The repression of transcription by ELL has been demonstrated to be due to its physical interaction with Pol II and the disruption of the formation of pre-initiation complex.113

The MLL gene is a recurring target for translocation in a variety of leukemias.59 It encodes a large, multidomain 3968-amino acid protein containing an N-terminal A-T hook DNA-binding domain, a methyltransferase-like domain, and a C-terminal trithorax-like region.59,114,115 The breakpoints in every MLL translocation create a putative oncogene that encodes nearly the entire translocation partner fused to the N terminus of the MLL protein, and each is associated with a clinically distinct form of leukemia.109

The MLL/ELL translocation found in patients with AML results in the deletion of a portion of the functional domain required for inhibition of promoter-specific initiation by ELL in patients with AML.105,106,113 In this chimeric protein, the N-terminal AT-hook DNA binding domain and the methyltransferase-like domain of MLL is fused to almost the entire ELL sequence.105,106 Deletion of the functional domain of ELL, which negatively regulates polymerase activity in promoter-specific transcription initiation in vitro,113 occurs in the MLL/ELL translocation and results in the bypass of the normal regulation of the transcriptional inhibitory activity of ELL.109 Each of the eight MLL translocations are associated with a clinically distinct form of leukemia, however the MLL/ELL translocation is the only one which has been characterized with respect to its biochemical activities.109 The distinct leukemic phenotypes seen with these translocations suggest that the specific translocation partner, such as ELL, and its normal biological function plays a major role in determining the leukemic phenotype.109


CREB (cAMP response element binding protein) binding protein (CBP) and p300 are closely related transcriptional co-activators that mediate target gene activation through their role in modulating initiation of transcription by RNA polymerase II complexes.116,117,118,119,120,121,122 Both p300 and CBP were originally identified through protein interaction assays. The association between p300, mapped to 22q13,117 and E1A, an adenoviral-transforming protein, led to p300 identification, while CBP, located on 16p13,123 was identified through its association with CREB.116

Both CBP and p300 contain three zinc finger domains, a CREB binding domain, a bromodomain, and a glutamine-rich region124 and play a role in many cell differentiation and signal transduction pathways.121,125,126,127,128 They have been shown to regulate gene expression and differentiation in hematopoietic cells through their involvement in leukemia-associated chromosomal translocations.129 For example, the CBP gene was found to be fused with the MOZ gene in AML patients with the t(8;16)(p11;q13)123,130 and with MLL (mixed lineage leukemia) in myelodysplastic syndrome (MDS) patients with t(11;16)(q23;p13).131 The p300 gene has been identified to be fused to the MLL gene, with the resulting fusion protein being generated in AML with t(11;22)(q23;q13).132 It has been postulated that the basis for the leukemogenesis of t(11;22)-AML is the inability of p300 to regulate cell cycle and cell differentiation after fusion with MLL.132

CBP and p300 function as co-activating proteins for several transcription factors including AML-1,133 Tal-1,134 and CREB.135 CREB, a 43 kDa protein and member of the CREB/ATF-1 family, is a central transcription factor that mediates cyclic AMP (cAMP) and calcium-dependent gene expression through the cAMP response element (CRE).136,137 CREB belongs to the CREB/activating transcription factor (ATF) family of transcription factors, which all bind to the CRE promoter. The CRE consists of an 8-bp sequence (TGACGTCA) and is usually located 100 nucleotides upstream from the TATA box in promoters of certain genes.138,139

CREB family members contain a domain responsible for DNA binding and dimerization, the basic leucine zipper (bZIP), and may contain the kinase-inducible domain (KID) containing several consensus phosphorylation sites, and two glutamine-rich transactivation domains.140 CREB is activated through phosphorylation at serine 133 following activation of the serine/threonine kinase pp90RSK (ribosomal S6 kinase) in response to GM-CSF.141 pp90RSK was shown to be activated in response to GM-CSF in the human myeloid leukemic cell line TF-1142 via an MEK-dependent signaling pathway.141 cAMP has also been shown to stimulate cellular gene expression through the protein kinase A (PKA)-mediated phosphorylation of CREB at Ser133.143 This enhances the transactivation potential of CREB by promoting the recruitment of the coactivators CREB-binding protein (CBP) and p300.144,145 In vitro transcription studies show that Ser133 phosphorylation of CREB is sufficient to recruit CBP-RNA polymerase II complexes and to induce transcription from a cAMP-responsive promoter.146

The activation of CREB is required for the induction of specific genes by growth factors, for example, c-fos by nerve growth factor (NGF)147,148 and egr-1 by the granulocyte-macrophage colony-stimulating factor (GM-CSF). Egr-1 is critical in the signal transduction pathway leading to the transcription of myeloid-specific proteins that function as determinants of myeloid cell differentiation.149,150

In various cell types, elevation of intracellular cAMP levels is associated with an arrest of proliferation in G1 and the induction of cell differentiation.151,152 In this way, CBP/p300 play a role in differentiation by virtue of their specific binding to CREB, which is phosphorylated by cAMP-dependent protein kinases116 thereby linking CREB to the basal transcription machinery.132


The c-myc gene and the expression of c-Myc are frequently altered in human cancers. The constitutive activation of c-myc is essential to the genesis of many cancers153 and high expression of c-myc is associated with proliferation and a block in differentiation.154,155 The oncogenic potential of myc can be activated by chromosomal translocation, retroviral insertion, or gene amplification.156 C-Myc heterodimerizes with another basic helix-loop-helix protein called Max to regulate gene expression.153 The t(8;14) translocation seen in Burkitt's lymphoma juxtaposes a portion of the MYC gene adjacent to the immunoglobulin gene leading to an aberrant expression of a normal MYC protein.59 This provided genetic evidence of the genes involved in chromosome translocations and validated the idea that they play a critical role in the development of lymphomas, leukemias and sarcomas.59

C-myc belongs to the family of myc genes, which include L-myc and N-myc, which also have oncogenic potential, as well as B-myc and S-myc.154,157,158,159,160,161 C-myc is located at human chromosome 8q24.162 This gene encodes both a 64 kDa polypeptide which is initiated at the canonical AUG start codon, and a 67 kDa polypeptide initiated 15 codons upstream of the AUG at a CUG codon.153 The c-Myc protein contains an N-terminal transactivation domain and a C-terminal dimerization interface consisting of a helix-loop-helix leucine zipper domain.153

The c-myc gene was discovered as the cellular homologue of the retroviral v-myc oncogene,163,164,165,166 and its regulation of the cell cycle takes place in early G1 phase or G1/S transition, promoting cell cycle progression.153 Some genes that have been proposed to be activated by Myc include cad, cdc25a, odc, elF-4E, and ISGF3gamma.156 However, it is thought that critical Myc target genes will be found to include both those that are activated by and those that are repressed by Myc.156 In addition, studies have shown a role for c-myc in development and cell proliferation. Targeted homozygous deletion of the murine c-myc gene resulted in embryonic lethality at 10.5 days of gestation.167 The homozygous inactivation of c-myc in immortalized rat fibroblasts caused prolongation of doubling time and accumulation of cells in the G1 and G2M phases of the cell cycle.168

Normally, the c-myc gene is tightly regulated, however, upon translocation with one of three immunoglobulin genes on chromosome 2, 14, or 22 it is constitutively activated in B cell malignancies169 and is thought to be critical in the development of lymphoid malignancies. Chromosomal translocations involving the c-myc gene occur in virtually all Burkitt's lymphomas170 and point mutations in the coding sequence of c-myc have been found in translocated alleles of c-myc in Burkitt's lymphomas.171,172,173 These mutations are thought to interfere with phosphorylation and thereby block negative regulation of c-Myc activity.174,175,176

Other transcription factors that have been implicated in the involvement of AML induction are the fusion protein ERG/TLS, and the transcription factor STAT, which are detailed below. The AML1/Evi-1 translocation (Figure 2b) has been identified in patients with AML and is associated with poor prognosis and abnormal megakaryopoiesis,177 as discussed below. Recently, a new ETV6/TEL partner gene, ARG (ABL-related gene or ABL2) was identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation.178

Chronic leukemias


TEL/JAK2 (translocated Ets leukemia/Janus kinase 2) fusion protein (Figure 3a) is found in both lymphoid and myeloid leukemias, and further implicates the involvement of the cytokine-signaling pathway in oncogenesis. In early B-precursor acute lymphoblastic leukemia (ALL), t(9;12)(p24;p13) translocations were found to be responsible and in atypical chronic myeloid leukemias (CML) a complex t(9;15;12)(p24;q15;p13) translocation was identified.179

The JAKs are receptor-associated tyrosine kinases involved in intracellular signaling pathways of several cytokine and growth factor receptors and are located on chromosome 9p24. JAK proteins share seven JAK homology regions, which include a region with tyrosine kinase activity and a regulatory region.180 The cytokine-induced activation of JAKs is responsible for the phosphorylation of multiple tyrosine residues in both the JAK kinase and in the cytoplasmic domain of the associated cytokine receptor.181 These phosphorylated tyrosine and adjacent residues serve as docking sites for a variety of intracellular signaling adaptors and effectors, including specific members of the STAT family of transcriptional regulators (discussed below).181

The TEL gene (also known as ETS-variant gene 6 or ETV6) is located at 12p13 and encodes a member of the ETS family of transcription factors. It was initially identified as the fusion partner of the gene encoding the platelet-derived growth factor-beta receptor in the t(5;12)(q31;p13) translocation in patients with chronic monocytic myeloid leukemia.182 It is affected in more than half of the abnormalities of the short arm of chromosome 12 in many hematopoietic malignancies and in solid tumors.183 The Ets family of transcription factors share a unique 85 amino acid DNA binding domain, the ETS domain.184 The Ets family is described in more detail with PU.1, another ETS family member described below. TEL functions as a sequence-specific DNA-binding transcriptional regulator.185 TEL also contains a 65 amino acid N-terminal helix-loop-helix (HLH) domain, called the pointed domain that is found in only a few Ets family members. This mediates homotypic oligomerization and appears to be critical for normal function.186,187,188,189,190,191 TEL is normally expressed not only in hematopoietic tissue, but also in non-hematopoietic tissue where it has been shown to be required for the maintenance of the developing yolk sac vascular network and for the survival of selected cell populations.186,192 Experimental evidence has also shown that TEL, unlike other transcriptional proteins, is specifically required for hematopoiesis.186,193

Evidence of the involvement of JAK kinase signaling in leukemia was established through the fusion of JAK2 to TEL in several cases of ALL, leading to the expression of the TEL/JAK2 fusion protein.179,194,195 In each case, the amino-terminal region helix-loop-helix oligomerization domain of the transcription factor TEL is fused to the catalytic JAK homology domain of JAK2 which leads to the constitutive activation of Stat proteins.195,196 The NH2-terminal conserved region (NCR) of TEL has been shown to mediate homotypic oligomerization of the TEL/JAK2 protein leading to constitutive tyrosine activity of its JAK2 moiety.180 This activates the transforming properties of TEL/JAK2 based on its ability to induce cytokine-independent proliferation. The growth factor dependency of murine hematopoietic Ba/F3 cells that are normally dependent on IL-3 for survival and proliferation is lessened, a characteristic thought to be critical for the transforming properties of other tyrosine kinase fusion proteins, such as TEL/ABL.189,194 Furthermore, TEL/JAK2 transgenic mice developed a fatal T cell leukemia at 4 to 22 weeks of age.181

TEL is involved in several other translocations. The t(12;21)(p13;q22), translocation fuses TEL amino-terminal residues to AML1, which is described below. Recently, a t(1;12)(q21;p13) translocation was characterized in a case of AML-M2. This translocation fuses the amino-terminal part of TEL to almost the entire gene encoding the aryl hydrocarbon receptor nuclear translocator (ARNT).183


The t(16;21)(p11.2;q22.2) translocation is found in myeloid leukemia and is associated with a poor prognosis in human AML, secondary AML associated with myelodysplastic syndrome (MDS), and CML in blast crisis.197,198 It juxtaposes the TLS/FUS (TLS) gene on chromosome 16 and the ERG gene on chromosome 21 and forms the TLS/ERG fusion gene (Figure 3b).199

The TLS (translocation liposarcoma) gene was originally identified at the site of the t(12;16) translocation in malignant liposarcomas, where it is fused to the CHOP (c/EBP homologous protein) gene.200,201 It encodes an RNA-binding protein and is located on chromosome 16.200 TLS contains a zinc finger motif and a SYGQQS degenerative repeat region, as well as three RGG repeat regions and an RNA-recognition motif, which are involved in its RNA binding activity.202 The normal cellular function of TLS is still unclear, however, it belongs to a family of proteins with members (EWS and TAFII68) that interact with the RNA polymerase II complex, suggesting a possible involvement of TLS in transcriptional activation.203

The ERG (ETS-related gene) gene encodes a transcriptional activator of the external transcribed spacer (ETS) proto-oncogene family and is located on chromosome 21.204 It contains a transactivator domain, the ETA domain, located in the N-terminal region, and a DNA-binding domain, the ETS domain, located in the C-terminal region.205

The chimeric protein that is produced by the fusion gene TLS/ERG contains an altered transcriptional activating and DNA binding domain. The ETS DNA-binding domain is retained and the ETA domain of ERG is replaced by the TLS/FUS N-terminal region198,199 and is thought to be responsible for the genesis and progression of t(16;21)-associated human myeloid leukemias.202 The mechanisms by which TLS fusion proteins lead to transformation are not yet established, although a recent study has shown that both TLS and TLS/ERG fusion proteins bind to RNA polymerase II through the TLS N-terminal domain, which is retained in the fusion protein.203 However, TLS/ERG inhibits RNA splicing mediated by serine-arginine proteins due to loss of the C-terminal domain by the fusion partner ERG and is therefore unable to recruit serine-arginine proteins.203

TLS/ERG expression has been shown to induce oncogenic activity similar to that seen in the human myeloid leukemias. Retroviral transduction of TLS/ERG in human cord blood cells has been demonstrated to alter myeloid, and arrest erythroid, differentiation, as well as increase the proliferative and self-renewal capacity of transduced myeloid progenitors.206 These data suggest that TLS/ERG alone was sufficient to initiate a leukemic program in normal human hematopoietic cells.206


The STAT (signal transducer and activator of transcription) proteins are latent cytoplasmic transcription factors that affect gene expression via the activation of the Janus kinases (JAK) and the subsequent recruitment of STAT to an activated receptor complex. JAK2 gene rearrangements have been found in human leukemias, suggesting a role of the JAK-STAT pathway process of leukemogenesis.180 In addition, TEL/JAK2-induced leukemia displays constitutive activation of STAT1 and STAT5.181

Stat proteins are selectively recruited in response to several cytokines, including erythropoietin, IL-3, and granulocyte-macrophage colony-stimulating factor207 to various cytokine receptors through peptide binding mediated by their SRC homology 2 (SH2) domains.208 There they form homodimers or heterodimers, become tyrosine phosphorylated and subsequently translocate to the nucleus where they regulate transcription. Seven Stat proteins have been identified in mammalian cells which all encode distinct genes.209 Although different STAT complexes are responsible for specific gene expression, they all bind to similar DNA response elements210 and are involved in cytokine and growth factor signaling.211,212 Stats have been shown to be important in the development and function of hematopoietic cells and a number of studies have provided evidence for a role of Stats in the transformation process.

In CML, the BCR gene from chromosome 22 is fused to the ABL gene from chromosome 9, forming the Bcr/Abl fusion product.213 STAT5 is constitutively activated in Bcr/Abl-expressing cell lines.214 STAT5 activation is involved in anti-apoptotic activity and cell cycle progression induced by Bcr/Abl and has been shown to be important for Bcr/Abl-mediated leukemogenesis both in vitro and in vivo.214 When expressed at high levels, a truncated form of STAT 5B, lacking tyrosine 699 and the transcriptional activation domain inhibited STAT5 activity. The growth rate of Bcr/Abl-transformed cells was reduced by inhibiting the viability, and resulted in increased sensitivity to chemotherapeutic drugs, suggesting that STAT5 activation plays a role in the transformation of hematopoietic cell lines by Bcr/Abl.215

In addition, constitutive activation of JAKs and STATs were identified in nuclear extracts of AML patients208 and transformed cell lines,180 linking the JAK-STAT pathway to the malignant phenotype. Constitutive STAT activation appears necessary, if not sufficient, for the transformation process.216 STAT5 activation was observed in cells transformed by all TEL/JAK kinases (described above) and shown to be essential for the mitogenic properties of TEL/JAK2 fusion protein, which is implicated in the leukemic process.181

STAT1 and STAT3 have been found to be phosphorylated on serine residues in 100% of CLL patients.217 B cell chronic lymphocytic leukemia (B-CLL) cells accumulate in vivo in G0/G1 phase of the cell cycle, suggesting that their malignant expansion is due in part to a delay in cell death.218 The interleukin-10 (IL-10) receptor has been shown to induce apoptosis in B-CLL.218 Ligand binding and activation of the IL-10 receptor expressed on B-CLL cells resulted in the tyrosine phosphorylation of STAT1 and STAT3 proteins,218 further linking the activation of STAT proteins to the pathogenesis of CLL.

Also involved in CLL is the transcription factor c-Myc, which has been discussed above.

AML1/Evi-1, AML1/MDS1/Evi-1

The fusion proteins AML1/Evi-1 (Figure 2b) and AML1/MDS1/Evi-1, t(3;21), are found in blast crises of chronic myeloid leukemia219 and the latter is also seen in some cases of newly diagnosed and therapy-related myelodysplasia/acute myelogenous leukemia.220,221 This translocation, as in the fusion protein AML1/ETO, involves the transcription factor AML1, described above.

The transcription factor Evi-1, is located on chromosome 3q26 and is a conserved DNA-binding proteins that belongs to the Kruppel family of proteins, containing two Cys2-His2 repeat zinc finger motif domains.222,223 The proximal domain of seven zinc fingers recognizes a DNA consensus site with a central AGATA motif.224,225,226 Evi-1 was first identified as the site of retroviral integration associated with myeloid leukemia in mice.222 It is normally not expressed in hematopoietic tissues, however, it is abnormally expressed in the retroviral induced leukemias in mice and in some human leukemias.227 Also located on chromosome 3, is the MDS/Evi-1 gene that is highly homologous to Evi-1. MDS/Evi-1 has an N-terminal extension that is missing in Evi-1. Evi-1 is often activated inappropriately by chromosomal rearrangements such as t(3;21), that lead to abnormal expression of the protein and to myeloid leukemias.177

In the fusion protein AML1/Evi-1, AML1 retains the runt DNA binding domain, however it lacks the putative transcriptional activation domain the proline-, serine-, and threonine-rich region.68 The Evi-1 gene segment is left intact. In the chimeric protein, the normal DNA binding and transactivation activity of AML1 is suppressed as a result of the competition for DNA binding between AML1 and AML1/Evi-1. Due to the higher affinity of AML1/Evi-1 for the binding site, the fusion protein acts as a dominant-negative.228 Expression in 32D cells induces apoptosis and inhibits granulocytic differentiation induced by granulocyte colony-stimulating factor (G-CSF).228 This block in differentiation of AML1/Evi-1 transfected cells is thought to be consistent with the differentiation arrest that characterizes the chronic phase to blast crisis transition in CML.68

In Rat-1 fibroblast cells, AML1/MDS1/Evi-1 has been shown to block granulocyte differentiation of the IL-3-dependent 32D cell line when stimulated with G-CSF.229,230 In a recent study, the human AML1/MDS1/Evi-1 fusion gene was expressed in mouse bone marrow cells using a retroviral transduction in order to study the in vivo effect of the fusion gene, as well as develop a molecular model for human AML. The fusion protein induced an AML similar to the human disease.227

Other transcription factors implicated in chronic leukemias are AML1 and WT-1 (described above), and PU.1 (described below).

Acute promyelocytic leukemia


Acute promyelocytic leukemia (APL) is known to be associated with at least five types of non-random reciprocal chromosomal translocations which always involve the retinoic acid receptor alpha gene (RARalpha) on chromosome 17. The majority of APL patients carry chromosomal translocation t(15;17), that fuses RARalpha to the promyelocytic gene PML.231,232,233,234 The fusion genes encoding PML/RARalpha (Figure 4a) and RARalpha/PML fusion proteins are generated.231,232,233,234

RARalpha encodes one of the retinoic acid receptors235,236 and belongs to a superfamily of nuclear hormone receptors. Members of this family exhibit physiological processes such as differentiation and growth arrest of various cell types.237,238,239 Both of the retinoic acid receptors, which bind both all-trans retinoic acid (ATRA) and 9-cis retinoic acid, and the retinoid X receptors, which only bind 9-cis retinoic acid, regulate retinoid activity.240

The PML gene was originally cloned as the t(15;17) chromosomal translocation partner of RARalpha in acute promyelocytic leukemia. The PML gene encodes a tumor suppressor protein associated with the nuclear body, where it is localized. PML is a member of the RING finger family of proteins, on chromosome 15 band q22.231,232,234 The PML protein is typically found concentrated in discrete nuclear speckles along with other proteins, which were originally identified as autoantigens in primary biliary cirrhosis patients.241 PML does not bind DNA directly, however, when tethered to DNA, its RING B-box coiled-coil (RBCC) domain displays a cryptic transactivating activity, which is dependent on the presence of the RING finger,242 whereas full length PML inhibits transcription.243 This suggests that the conformation of PML and/or its interactions with other proteins determine its transcriptional activity.244

PML exhibits multiple biological functions. It is a mediator of interferon function and immune surveillance, it acts as a pro-apoptotic factor, and it also acts as a tumor suppressor.244 The biochemical role of PML is still unclear, however, recent findings indicate that PML is essential for the proper formation of the nuclear body and can act as a transcriptional cofactor.245,246 PML acts as a transcriptional co-activator in the RARalpha/RXRalpha transcriptional complex.244

Biological effects of PML/RARalpha protein seem to be responsible for the some of the critical features of the APL phenotype, which is the accumulation of hematopoietic precursors blocked at the promyelocytic stage of differentiation.247 The majority of patients with this type of fusion respond to retinoic acid (RA) induced differentiation therapy.248

Normally, RARalpha can dimerize with retinoid X receptors (RXRs) in the enhancer/promoter region of specific target genes and activate transcription.7 In the absence of ligand retinoic acid, basal transcription is repressed due to the association of RAR/RXR heterodimers with transcriptional co-repressors. Transcriptional repressors and histone deacetylases are then recruited which result in the nearby chromatin being inaccessible to transcriptional activators and thus repress basal transcription.7 ATRA (all-trans retinoic acid) treatment causes the induction of dissociation of the co-repressor complex, recruitment of co-activators to the transcriptional complex, and activation of gene expression.7 Both PML/RARalpha and PLZF/RARalpha are considered RAR mutants because of their ability to mimic this wild-type RARalpha activity.249,250,251


In addition to RARalpha fused to PML, it can also form fusion proteins with four other genes, promyelocytic leukemia zinc finger gene (PLZF),252 nucleophosmin gene (NPM),253 STAT5b,254 and nuclear mitotic apparatus gene (NuMA).255 The RARalpha/PLZF gene, on chromosome 11 band q23, encodes a transcriptional repressor that contains an N-terminal POZ motif and a C-terminal DNA binding domain consisting of Kruppel-like C2-H2 zinc fingers.252 The fusion protein contains the RARalpha DNA, ligand, co-repressor, and co-activator binding domains fused to the PLZF gene7 (Figure 4b).

PLZF was originally identified as a human oncogene, which is activated via its involvement in a chromosomal translocation, t(11;17). This zinc-finger transcription factor is expressed in immature hematopoietic cells.210 In non-leukemic systems, it has been implicated in the development of the central nervous system and it can bind to defined DNA sequences.256 Due to the presence of interdigitated DNA recognition and co-repressor domains, it has been suggested that DNA binding may influence its transcriptional repression properties,256 and in transfection assays, it has been shown to mediate repression in cells.256 Additionally, PLZF exhibits the ability to interact with important components of the SMRT.N-CoR co-repressor complex.256

Unlike the PML/RARalpha fusion protein, PLZF/RARalpha is not affected by therapy with ATRA as a result of its association with the co-repressor proteins SMRT, mSin3, and histone deacetylase-1 (HDAC).256 Upon forming the chimeric protein PLZF/RARalpha several important co-repressor sites are lost and the resulting oncoprotein has distinct regulatory properties from either parental protein.256 Aberrant interactions between chimeric RARs and the SMRT.N-CoR co-repressor complex have been postulated to be the basis for their oncogenic phenotype.257,258,259,260

The PLZF/RARalpha has undergone a number of changes as a result of the translocation. The C-terminal PLZF sequences have been deleted, weakening the interaction with HDAC-1 and with the N-terminus of SMRT, thus exhibiting weakened transcriptional repression of the isolated PLZF fragment.256 The t(11;17) translocation preserves the PLZF domains that interact with mSin3A, however this contact alone appears to be inadequate for efficient repression.256 Finally, the RARalpha sequences that replace the C terminus of PLZF in the fusion protein contribute an independent, strong SMRT interaction domain that is able to restore effective repression.256

The interaction between the RARalpha sequences and SMRT is disrupted by retinoic acid, however the co-repressor interactions conferred by the PLZF section are not affected by this hormone.257,258,259,260 This is thought to be a factor in the oncogenic properties of the fusion protein, as well as in the hormone-refractory nature of the associated t(11;17) translocation leukemias.256

Erythroid leukemia


PU.1 (Figure 5) is a hematopoietic specific member of the Ets family of transcription factors187,261 and is identical to the product of the Spi-1 proto-oncogene.91 It has been implicated in malignant processes such as erythroid leukemia and Ewing's sarcoma.262 Expressed in the earliest stages of both lymphoid and myeloid development, PU.1 appears to be required in order for myelomonocytic and B-lymphoid progenitors to develop.263 In addition, PU.1 is expressed in monocytes/macrophages, B-lymphocytes, erythroid cells, and granulocytes.91

The Ets family of transcription factors share a unique 85 amino acid DNA binding domain, the ETS domain.184 With the exception of GABPalpha, all Ets family members can bind DNA as monomeric proteins and form a winged helix-turn-helix motif which allows Ets proteins to interact with an approximately 10 bp long AGGAA/T containing DNA element.264 In PU.1, the ETS domain is found near the carboxy-terminal end.265

PU.1 was first identified as a protein that binds to a purine-rich sequence in the promoter of the mouse major histocompatibility complex (MHC) class II I-Abeta gene.265 The polyclonal expansion which leads to Friend virus-induced murine erythroleukemia (MEL) genesis is a result of the constitutive stimulation of erythropoietin receptor binding of the gp55 glycoprotein encoded by the env gene of spleen focus-forming virus (SFFV).266,267 PU.1 involvement in the malignant transformation of erythroid cells has been suggested based on its expression in MEL cells after proviral integration into the PU.1/Spi-1 locus. At the same time, inactivation of the p53 tumor suppressor gene by gene mutation, gene deletion, and/or SFFV proviral integration at the Spi-1 locus occurs.268,269,270

Overexpression of PU.1 induces growth and inhibits differentiation, as well as inducing apoptotic cell death in erythroleukemic cells. Recommitment of erythroid differentiation and loss of immortality of MEL cells coincides with a decrease in the amount of PU.1.271 Infection of bone marrow cultures with an Spi-1/PU.1-transducing retrovirus caused the proliferation of proerythroblast-like cells that differentiated at low frequency into hemoglobinized cells.272 When antisense oligonucleotides were used to reduce Spi-1/PU.1 expression in SFFV-transformed cell lines, there was a reduced proliferative capacity. In addition, characteristics of MEL induced by SFFV were seen in transgenic mice overexpressing Spi-1/PU.1.273 Therefore, PU.1 may contribute to the growth/self-renewal enhancement and the differentiation inhibition of the leukemic cells.

PU.1 also plays a role in regulating the hematopoietic transcription factor gene SCL (stem cell leukemia), also known as tal-1.274 The SCL gene encodes a basic helix-loop-helix transcription factor that is essential for the normal development of all hematopoietic lineages and was originally discovered through its involvement in a chromosomal translocation associated with T cell acute lymphoblastic leukemia (ALL).275,276,277,278 Rearrangements of the SCL locus are now realized to be the most common molecular pathology associated with T cell ALL and its downregulation may be necessary for normal monocytic differentiation.274 Furthermore, experimental data implicates SCL in regulating proliferation, differentiation, and apoptosis279 and it is thought that inhibition of apoptosis may underlie the leukemogenic effect of SCL expression in T cells.280 Other gene targets regulated by PU.1 include M-CSF receptor, neutrophil elastase, G-CSF receptor, GM-CSF receptor alpha, and PU.1.281

The development of myeloid-derived dendritic cells, an essential component in T-cell activation and in the initiation of an immune response requires the presence of PU.1.263 Additionally, the myeloid B-lymphocyte-deficient phenotype is associated with loss of function of the transcription factor PU.1.282 Finally, the phosphorylation of PU.1 has been implicated in the leukemic process. Research to fully elucidate its role in this process is ongoing.210,282,283,284,285,286,287,288,289,290 PU.1 is phosphorylated on serine residues 41, 45, 132 and/or 133, and 148.290

Acute lymphoid leukemia


E2A/Pbx1 (Figure 6a) is a chimeric oncoprotein produced by the t(1;19)(q23;p13.3) chromosomal translocation.291,292,293 It has been identified in 5-10% of human acute leukemias (294), and in 10-20% of human pediatric pre-B acute lymphoblastic leukemias.291,292,293 Transformation assays have shown that E2A/Pbx fusion protein is oncogenic.295,296

Pbx1 belongs to a family of related homeobox genes, which include Pbx2 and Pbx3.297 The Pbx family of homeodomain (HD) proteins have been shown to contribute to the transcriptional and developmental roles of other Hox proteins through heterodimer formation,298,299,300,301 and are potential regulators of hematopoietic proliferation and differentiation.302 When Pbx proteins form complexes with the Hox proteins, their DNA-binding affinity and specificity are increased.303,304,305,306 E2A exhibits multiple transforming properties. In NIH 3T3 cells, it has the ability to induce the formation of foci, anchorage-independent growth, and tumor formation in nude mice.307

In this fusion protein, exons encoding the N-terminal transactivation domain of the basic helix-loop-helix transcription factor E2A are fused to exons encoding the homeodomain of Pbx1, Pbx2, and Pbx3.297 In Pbx1, this fusion begins at residue 89.298 Most of the Pbx1 coding sequence, which includes the HD, is fused to the 5' half of the E2A gene, which encodes two transcription activation domains but lacks both the DNA binding and dimerization domains of E2A.292,293

In thymocytes and myeloid cells, aberrant expression of E2A/Pbx1 promotes the rapid development of T cell lymphomas and myeloid leukemias,295,296 yet Pbx1 has no detectable transactivation potential.308 Therefore, the oncogenic potential of E2A/Pbx1 may be caused by the inappropriate activation of genes normally regulated by Pbx/Hox complexes.309 Collaboration between E2A/Pbx1 and Hoxa9, a presumed DNA binding partner of E2A/Pbx1a, was shown to be sufficient to acutely transform primary bone marrow cells.294 Overexpressing individual Hox proteins each showed different, lineage-specific effects on the proliferation and differentiation of hematopoietic stem cells or committed progenitors.310,311 The heterodimer formed with E2A/Pbx and Hox produces acute myeloid leukemia in mice, and blocks differentiation of cultured murine myeloid progenitors.298 E2A/Pbx1 fusion proteins lack all Pbx1 sequences N- of C-terminal to the HD, but retain a myeloid phenotype suggesting that Hox proteins, or an unidentified factor, cooperate with E2A/Pbx1 in this immortalization through the binding of the Pbx1 HD and derepressing DNA-binding by the HD.298 Together, these gene products are thought to produce a highly aggressive acute leukemic disease.294


The t(12;21)(p13;q22), TEL/AML1 fusion gene, is the most common genetic abnormality in childhood pre-B cell acute lymphoblastic leukemia and is seen in approximately 20% of patients312 and is associated with a favorable prognosis.190 This translocation results in two chimeric genes: the TEL/AML1 fusion gene, which has consistently been detected in cells with t(12;21), and the AML1/TEL fusion gene. TEL is fused in frame to AML1.313 Both TEL and AML1 genes are the two most common targets of chromosomal rearrangements in both myeloid and lymphoid human leukemias.186

The t(12;21) chromosomal translocation is present in 25% of pediatric and 3% of adult B-lineage ALL.35 The TEL/AML1 chimeric gene expresses a fusion protein that contains the 333 NH2-terminal amino acid of the TEL (translocation, ets, leukemia, also known as ETV6) protein encoding the dimerization domain but lacking the ETS DNA-binding domain, which is linked to residues 21 to 480 of AML1-B, including the AML1 DNA-binding domain314 (Figure 6b).

The TEL/AML1 fusion protein can interact with AML1 DNA-binding sites and dominantly inhibit AML1-dependent transcription.315 This fusion protein can inhibit basal transcription from a promoter construct containing the T cell receptor beta enhancer (TCRbeta).35 In the majority of ALL cases containing TEL/AML1, the other allele of TEL is deleted, and in some cases both alleles are deleted, indicating that both copies may not be necessary initially for transformation.316,317 Analysis of the transcriptional regulatory functions of the t(12;21) fusion protein suggests that TEL acts as a tumor suppressor, with the altered TEL cooperating with the t(12;21) to induce leukemia.314,315 It is hypothesized that loss of TEL contributes to leukemogenesis by furthering the ability of TEL/AML1 to repress CBF-regulated genes.35

Also involved in ALL are WT-1, c-Myc, PU.1, STAT, and SCL which are described above.

Therapeutic significance

The characterization of the pathophysiology of leukemia has a direct impact on disease-specific treatment strategies, diagnosis, and prognosis. Identification of the molecular defects involved in the various subtypes of leukemia is required in order to direct cancer therapy treatments and to predict a patient's response to therapy successfully. The classification of distinct tumor types can aid in our ability to design more efficient cancer therapy programs and lead to disease specific cancer therapy targets.

In APL, ATRA (all-trans retinoic acid) treatment which was discussed previously in this review, targets PML/RARalpha and causes the induction of dissociation of a co-repressor complex, thereby releasing suppression of Sin3 and histone deacetylase from the transcriptional complex. Co-activators are then recruited to the transcriptional complex, and thus activation of gene expression and the onset of differentiation occur.7 Dissociation of the transcriptional co-repressors SMRT/N-CoR and recruitment of co-activators to APL-associated fusion proteins constitute a common molecular mechanism in APL and underlie the responsiveness of the disease to retinoic acid therapy.7

Combined therapy using ATRA and butyrate has been reported to induce complete remission of ATRA-resistant cells in the clinical setting.318 The fusion protein PLZF/RARalpha is unresponsive to treatment with ATRA due to its retinoic acid-insensitive interactions with co-repressors and histone deacetylase (HDAC), and is therefore still able to repress transcription. The development of inhibitors of HDAC as anti-leukemic drugs has been proposed.254 Histone deacetylase inhibitors have been found to be potent inducer/enhancers of differentiation in acute myeloid leukemia cells, and enhanced differentiation induced by ATRA therapy.319

AML-1/CBFalpha/ETO gene is both diagnostic for M2 AML and is a marker for favorable prognosis. Approximately 90% of t(8;21)-containing leukemias have been found to have FAB AML-M2 morphology and 30-40% of FAB-M2 cases have this chromosomal translocation.54 The presence of this translocation is associated with a high remission rate and prolonged disease-free survival in patients treated with induction and consolidation chemotherapy.54 TEL/AML1 is also considered to have a favorable prognosis186 and in addition, it is has been shown that treatment intensity in these cases affects the outcome.320

The expression of WT1 in acute leukemias (AL) and blast crisis of chronic myelocytic leukemia has been reported.18,19,321,322,323 Since the WT1 protein plays an essential role in the growth of leukemic and solid tumor cells, loss of expression of the WT1 protein results in cessation of the proliferation of leukemic and solid tumor cells.11 In addition, mutations of the WT1 gene in acute leukemia have been found in about 15% of cases and have been associated with a poor prognosis.324 Experimental evidence has shown that T lymphocytes specific for CD34+ progenitor cells may be critically important in mediating antileukemic effects in patients with CML.325 Recently, the WT1 protein was identified as a novel tumor antigen and therefore a candidate for clinical application of WT1 protein-directed immunotherapy for patients with both leukemia and solid tumors.11 WT1 has been found to be a target for cytotoxic T lymphocytes (CTL) with specificity for leukemic CD34+ progenitor cells, which not only makes WT1 a good target for antigen-specific therapy in vivo, but also for CTL-mediated purging of leukemic progenitor cells in vitro.28

Further investigation is necessary in order to further characterize leukemias and expand our understanding of the mechanisms of leukemogenesis. Through the ability to conform therapy to individual patients, their chance for a cure is increased.


Cytogenetic and molecular studies of leukemia have led to the identification of a variety of genetic alterations such as chromosomal translocations and the aberrant expression of key cellular regulatory elements. Alterations in the signaling pathways of cells have the potential to induce oncogenic change in these cells. Transcription factors are a common target for oncogenic activity that results from chromosomal abnormalities, and through their role in maintaining transcriptional regulation in the hematopoietic system, are thus involved in the development of leukemia.


We thank Patricia Mora-Garcia and Jorge Vargas for their suggestions and assistance in editing. This work was supported by National Institute of Health Grant CA68221-03 and American Cancer Society Grant RPG 99-081-01-LBC. KMS is a Scholar of the Leukemia and Lymphoma Society.


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Figure 1  Diagram of hematopoiesis.

Figure 2  (a) The structure of the t(8;21) product. It includes the AML1 central Runt homology DNA-binding domain (RHD), and almost the entire ETO protein. The ETO regions are an N-terminal domain with homology to transcription-activating factors (TAF), a hydrophobic heptad repeat (HHR), the Nervy homology region 3 (NHR3) that is homologous to the ETO group of proteins, and two zinc finger motifs (ZFD). (b) The structure of the t(3;21) product containing the RHD of AML1 as well as a non-coding region (NCR), two zinc finger domains (ZFD), a repression domain (RD), and an acidic domain (AD) of Evi-1. Molecular weight (MW) of the chimeric proteins has been indicated.

Figure 3  (a) In TEL/JAK2, the helix-loop-helix oligomerization domain (HLH) of the transcription factor TEL is fused to the catalytic Jak homology domain (CJH) of Jak2. (b) The t(16;21) product contains an SYGQQS repeat region (SYGQQS), and RGG repeat region (RGG) and the ERG ETS domain (ETS). The fusion proteins molecular weight has been indicated.

Figure 4  (a) The fusion product PML/RARalpha, generated by t(15;17), contains a proline rich domain (P), a cysteine-histindine-rich RING finger and B-box domain (CHD), an alpha helix domain (alphaHD), a DNA-binding domain (DBD), and a ligand-binding domain (LBD). (b) PLZF/RARalpha contains an N-terminal POZ motif (POZ), potential proline-dependent phosphorylation sites (PPS), and Kruppel-like zinc fingers (ZFD), as well as the DNA- and ligand-binding domains of RARalpha. The molecular weights of both chimeric proteins have been indicated.

Figure 5  The sequence of the PU.1 protein includes the activation domain (AD), the site of phosphorylation that influences protein-protein interactions (PPP), and the ETS domain at the carboxyl-end of the molecule. The molecular weight of the PU.1 protein has been indicated.

Figure 6  (a) Structure of E2A/Pbx1a and E2A/Pbx1b. The chimeric protein includes the E2A transactivation domain (TD) and the DNA binding/dimerization domain (DBD) in addition to the Pbx1 homeodomain (HD) and in E2A/Pbx1b, a unique COOH-terminal sequence (CTS). (b) The helix-loop-helix domain (HLH) of TEL is fused to the AML1 Runt homology domain (RHD), a proline-serine-threonine rich domain (PST), a nuclear matrix targeting signal (NMTS), and a transactivation domain in TEL/AML1. The molecular weight of each has been noted.


Table 1  Transcription factors involved in leukemia

Received 7 August 2000; accepted 6 October 2000
March 2001, Volume 15, Number 3, Pages 313-331
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