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Chronic myelogenous leukemia: mechanisms underlying disease progression

Leukemia volume 16, pages 1402–1411 (2002)Cite this article

Abstract

Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABL-mediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed as increased oncogenic activity or loss of tumor suppressor activity. However, what causes transformation and disease progression to blast crisis is only poorly understood. This is in part due to the lack of a good in vivo model of chronic phase CML even though animal models developed over the last few years have started to provide insights into blast crisis development. Thus, additional in vitro and in vivo studies will be needed to provide a complete understanding of the contribution of BCR-ABL and other genes to disease progression and to improve therapeutic approaches for blast crisis CML.

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Introduction

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of the hematopoeitic stem cell (HSC). In the initial chronic phase, myeloid progenitors and mature cells accumulate in the blood and extramedullary tissues.1 After 3–4 years, the disease transforms and terminates in a blast crisis characterized by a maturation arrest in the myeloid or lymphoid lineage.2,3,4 The only curative therapy for this disorder is allogeneic stem cell transplantation performed during chronic phase.5,6,7 Treatment with interferon α delays progression of the disease to blast crisis and in 10–20% of patients results in complete remission.6,8 The median survival of patients with blast crisis without treatment is 3 months.3

CML is a malignancy that is consistently associated with an acquired genetic abnormality, the Philadelphia chromosome. Ph is present in >90% of patients and is the result of a rearrangement between the BCR and Abelson genes. The BCR-ABL fusion gene, is seen in up to 95% of CML patients and gets translated into an oncoprotein, p210BCR/ABL.9 The presence of p210BCR/ABL is necessary and sufficient for malignant transformation as demonstrated in animal models10,11,12,13 and in vitro systems.14,15 Although the molecular mechanisms that underlie BCR-ABL-mediated transformation have been extensively studied, progression of the disease from chronic phase to blast crisis is incompletely understood. In this review we will summarize the patho-physiology of chronic phase CML as it is currently understood and then discuss the molecular mechanisms thought to contribute to the progression of chronic phase to blast crisis CML.

Molecular biology of BCR-ABL

Approximately 90% of patients with CML have an acquired genetic abnormality, the Philadelphia chromosome (Ph).16 The Ph is a shortened chromosome 22 resulting from a reciprocal translocation between the long arms of chromosomes 9 and 22 t(9; 22q34;q11).16,17 In this translocation, the c-ABL proto-oncogene is transposed from its normal position on chromosome 9 to a 5.8 kb major breakpoint cluster region M-BCR on chromosome 22, forming a BCR-ABL fusion gene.17,18 The new gene encodes p210BCR/ABL, an oncoprotein that has increased tyrosine kinase (TK) activity19,20 and increased binding to the actin cytoskeleton21 compared with the p145 Abelson protein, both of which contribute to transformation. The presence of p210BCR/ABL causes growth factor independence and leukemic cell growth in hematopoietic cell lines.14,15,22 Transplantation of BCR-ABL-transduced hematopoietic stem cells or transgenic expression of p210BCR/ABL induces leukemia, lymphomas and CML-like syndromes10,11,12,13,23,24,25,26,27 proving the direct causal relationship to CML.

Prior to discussing the biology of the BCR-ABL gene we will review the functions of the gene products of the normal Abelson and BCR genes. The p145ABL protein, the product of the Abelson gene, is a TK whose function is not totally known. There is evidence that p145ABL is important for cell growth,28,29,30 induction of apoptosis31,32,33 and is involved in DNA repair.34,35,36 Although p145ABL is found mainly in the cell nucleus, there is mounting evidence that it plays a role in cell signaling from integrins37 as well as other cell surface receptors such as the B cell receptor and CD19.38 Abelson−/− mice die early after birth due to severe runting and impaired lymphoid development39 that may be related to the recently discovered role of p145ABL in B cell function.38 ABL+/− mice, however, are normal indicating that it is unlikely that loss of one normal Abelson allele in CML plays a role in the disease. Even less is known about the function of the normal BCR gene.

BCR−/− mice develop septic shock when challenged with lipopolysaccharide due to a significantly increased and dysregulated neutrophilic oxidative burst.40 BCR +/− mice are normal, again suggesting that loss of one normal BCR allele does not play a role in the pathogenesis of CML.

Signal transduction in chronic phase CML

The biology of the BCR-ABL oncogene and its intracellular signal transduction pathways have been extensively reviewed41,42,43,44 and only the key parts will be discussed here (Figure 1). The BCR-ABL oncoprotein has constitutively expressed tyrosine kinase activity as a result of oligomerization of the coiled coil region of p210BCR/ABL 45 and deletion of the inhibitory SH3 domain of ABL.46 This results in phosphorylation of p210BCR/ABL itself on the Y-177 tyrosine residue47 and leads to recruitment of GRB2,48 a small adapter molecule that can activate the RAS pathway.49,50,51,52 p210BCR/ABL kinase also phosphorylates JAK2 and STAT1/STAT5,53,54,55,56 proteins that transfer signals from non-TK cytokine receptors to the nucleus. RAS and STAT activation contributes to growth factor independence of cell lines containing the BCR-ABL gene.

Figure 1
figure 1

CCM, coiled coil motif; Y-177, tyrosine residue; STK, serine-threonine kinase; SH1 and 2, Src homology domain; PPD, polyproline domain; F-actin, actin binding domain; FAK, focal adhesion kinase. Signal transduction pathways affected by p210BCR-ABL. Activation of the RAS, Jak/Stat and PI-3 kinase pathways results in increased proliferation, differentiation and decreased apoptosis of CML progenitors. F-actin binding via integrins results in impaired adhesion and premature release of CML progenitors into the circulation. Loss of p53 results in diminished apoptosis and increases the likelihood of secondary genetic abnormalities. Decreased DNAPKcs can result in inadequate DNA repair, as may decreased amounts of nuclear ABL. Shuttling of ABL occurs between the nucleus and cytoplasm and cytoplasmic ABL has a role in cell surface signaling through integrins. Cytoplasmic ABL is also believed to inhibit the PI(3)K pathway, a function that may be impaired due to reduced amounts of ABL.

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Furthermore, p210BCR/ABL activates the PI(3)K/Akt pathway,57,58,59,60 increases expression of BCL-2,61 and phosphorylates STAT562,63 leading to the increased resistance of CML progenitors to apoptosis.

Finally, p210BCR/ABL is localized almost exclusively in the cytosol due to loss of a nuclear localizing signal and has increased binding to actin compared with p145ABL.21,64,65 This results in phosphorylation of a number of neighboring cytoskeletal proteins including FAK66 and paxillin,67 all of which contribute to aberrant adhesion receptor function and may explain the premature circulation of progenitors and precursors in the blood.68,69

The features of chronic phase CML, expansion and premature circulation of the malignant myeloid population can therefore be explained by activation of mutagenic pathways, antiapoptotic pathways and abnormal cytoskeletal function (Figure 1). These same characteristics, increased mutagenicity and decreased susceptibility to apoptosis may also be responsible for disease progression.70 Moreover, the continuously proliferating malignant cell population is prone to secondary genetic abnormalities, which may be better tolerated due to the antiapoptotic phenotype conferred by the presence of p210BCR/ABL. Subsequently, multiple malignant clones with new genetic errors emerge that can ultimately lead to disease progression and blast crisis.

Mechanisms of disease progression

Although the BCR-ABL gene plays a central role in the pathogenesis of chronic phase CML and its continued expression is required for the proliferation of cells in the acute phase, the molecular events leading to the evolution to blast crisis are not fully understood. CML cells develop additional cytogenetic or molecular defects that commonly precede blast crisis (Table 1). The significance of these cytogenetic and molecular defects and their impact on disease transformation will be discussed in this section. We will also describe the underlying pathways that are considered important in disease progression.

Table 1 Cellular and molecular events associated with disease progression
Full size table

Cellular events

Decreased apoptosis

Apoptosis or programmed cell death can be considered a protective mechanism against cancer and its derangement has significance in many malignancies. Cells harboring or acquiring chromosomal errors by DNA damaging agents undergo apoptosis. Signals instructing a cell to undergo apoptosis are multiple, complex and highly redundant. The final decision for a cell to initiate apoptosis rather than cell cycle arrest, or a failure to respond by either method may be dependent on the magnitude and duration of the damage stimulus.

In CML, multiple mechanisms contribute toward resistance against apoptosis. Phosphorylation and activation of the PI(3)-K/Akt pathway59,71 is a major pathway by which BCR-ABL exerts its antiapoptotic effect. PI(3) kinase activation also via protein kinase B, results in the phosphorylation and inactivation of the pro-apoptotic protein BAD a member of the Bcl-2 family.60 Increased expression of BCL-2 the prototype member of the BCL family of antiapoptotic proteins72 has been described in cell types harboring the BCR-ABL oncogene and contributes to decreased apoptosis.61 BCR-ABL-mediated activation of STAT5 and subsequent increases in BCLxl levels may also increase resistance to apoptosis.62,63,73

Most but not all studies using p210BCR/ABL expressing cell lines have demonstrated that BCR-ABL expression protects from apoptosis induced by physical and chemical stresses.74,75,76,77,78 Additionally, chronic phase CML CD34+ cells undergo delayed apoptotic death upon cytokine withdrawal when compared with normal progenitors.79,80,81 The use of antisense oligonucleotides against BCR-ABL could reverse the delay in apoptosis in CML cell lines.80,81 P210BCR/ABL may protect cells from cytotoxic agent-induced apoptosis by preventing the release of cytochrome-c82 and preventing the activation of caspases especially caspase 3.83

The redox-sensitive transcription factor NF-κB translocates to the nucleus upon cellular activation and its activity is generally associated with protection from apoptosis. There is evidence for activation of NF-κB in transgenic models of CML which is yet another mechanism that may protect against apoptosis.84 Finally, the RAS pathway may be involved in BCR-ABL-mediated inhibition of apoptosis75,85,86 and elevated cytokine production87,88 may have an inhibitory effect on apoptosis.

Interestingly, c-ABL is thought to have a pro-apoptotic function in the cytoplasm by inhibiting the survival pathway mediated by PI(3)K and as discussed later, methylation of the only normal ABL allele seen during disease progression may contribute towards resistance against apoptosis. Nuclear ABL is also believed to have a role in cell death. More evidence to support this theory has emerged with the demonstration that nuclear import of BCR-ABL in a CML cell line by treatment with STI-571 (gleevec, a new specific tyrosine kinase inhibitor that inhibits the BCR-ABL TK at micromolar concentrations89) and its subsequent nuclear entrapment by leptomycin B induced apoptosis.90 Therefore, the abnormal cytoplasmic location of BCR-ABL and the reduction in nuclear ABL protein may enhance resistance to apoptosis.

Protection against apoptosis is relatively minimal in chronic phase CML but there is evidence that BCR-ABL mediates resistance to apoptosis in a dose-dependent fashion.91 Increased expression of the BCR-ABL mRNA, often associated with disease progression92 may therefore lead to increased resistance to apoptosis in accelerated phase and blast crisis.91 Despite being a characteristic feature of CML decreased apoptosis alone is not sufficient for disease transformation and disease progression likely requires additional abnormalities such as for instance, loss of a tumor suppressor gene.

Differentiation block

During the process of hematopoeitic differentiation, pluripotent stem cells become lineage committed and eventually differentiate morphologically and functionally into distinct blood cell types. Although the p210BCR/ABL itself does not significantly affect terminal cell differentiation in chronic phase, differentiation is blocked in blast phase CML.93,94,95 The role of BCR-ABL itself or other events in this phenomenon is not fully elucidated. Additional mutations, formation of new oncogenes, elevated cytokine levels, inactivation of tumor suppressor genes are hypothetical reasons for this phenomenon. As exemplified in acute promyelocytic leukemia, tumor progression can be suppressed by inducing differentiation with cytokines or factors that regulate normal hematopoiesis.96,97 Further studies elucidating the mechanisms underlying the differentiation block seen in blast crisis CML are warranted to help define a role for differentiating agents in the therapeutic armamentarium against blast crisis.

Decreased immune surveillance

MHC-restricted and MHC-unrestricted mechanisms play an important role in the natural control of the Ph clone in chronic phase as well as during progression of CML.98 Among the MHC-restricted mechanisms, T lymphocyte-mediated killing of target cells via Fas-receptor triggering plays an important role in elimination of malignant CML cells. CML progenitor cells also express functional Fas-ligand, which may be an important immune surveillance escape factor. In comparison to the chronic phase, CML cells derived from patients in blast crisis are refractory to Fas-mediated apoptosis, regardless of the expression levels of Fas, suggesting that an immune-mediated selection pressure could result in acquisition of Fas resistance.99,100 Natural killer (NK) and activated killer (AK) cells mediate MHC-unrestricted cytotoxicity. There is evidence for declining NK cell function in blast crisis CML but it is unclear if this is a cause rather than an effect of disease progression.101,102

Drug resistance

CML progenitors obtained from patients during chronic phase and blast crisis are equally sensitive to STI-571 by in vitro assay methods.103 Despite this observation there is a lower response rate in accelerated phase and blast crisis compared with chronic phase CML indicating development of drug resistance in vivo. The other possibility to consider is the presence of additional genetic errors that can stimulate the malignant clone in the absence of BCR-ABL. The observation that some patients who initially respond to STI-571 redevelop Ph-positive hematopoiesis may also indicate development of drug resistance. Additionally, resistance to interferon α or hydroxyurea is thought to be a herald of disease transformation. Drug resistance may be contributory to the change in character of chronic phase CML. There are multiple mechanisms involved in resistance to therapy, which could impact on disease progression. These include expression of the MDR-1 gene,104,105 AGP-1,106 reduplication of BCR-ABL or its overexpression,104,107 decreased apoptosis74 and possibly defective drug transport.

Genetic events

Cytogenetic and molecular changes occur in the majority of the patients during evolution to blast crisis. Approximately 70–80% of patients with classical Ph-positive CML show additional non-random chromosomal changes108,109,172 involving chromosomes 8, 17, 19 and 22 with duplication of the Ph chromosome108 or trisomy 83 being the most frequent. In about 15% of patients, progression of the disease is associated with −7, −17, +17, +21 and −Y.172

At the molecular level, the most frequent abnormality is a deletion of p53, a tumor suppressor gene located on the short arm of chromosome 17,110,111,112 leading chiefly to myeloid blast crisis. About 50% of patients with lymphoid blast crisis have a homozygous deletion of the p16INK4a gene located on chromosome 9.113 Other less frequent acquired genetic abnormalities are deletions of the retinoblastoma gene,114 overexpression of c-MYC115,116,117,118 or N-RAS119 and generation of an oncogene AML-EVI-1.120,121

Inactivation of tumor suppressor genes

DNA damage in eukaryotic organisms leads to activation of DNA damage sensor proteins such as ATM.122 These proteins when activated phosphorylate p53, which in turn upregulates expression of proteins such as BAX,123, CD95124 and DR5,125 all members of core apoptotic pathways. In addition, activated p53 causes increased expression of cell cycle blocking genes such as p21cip1,126 leading to cell cycle arrest at the G1–S phase to allow cell repair. Thus, the p53 gene manifests its tumor suppressive effects via apoptotic cell death or cell cycle arrest.126 The tumor suppressor role of p53 has been demonstrated in p53 knock out mice that develop normally but are prone to developing spontaneous tumors.127

The p53 gene is located on chromosome 17 and its inactivation has been shown to be important in the evolution of CML to blast crisis.128 Loss of p53 function can be due to mutations,129 deletions and rearrangements130 and is seen in 25% of myeloid blast crisis.111,129,131,132 In addition to loss of function mutations, the production of mutant p53 proteins can function as a dominant negative isoform or can act cooperatively with BCR-ABL to stimulate proliferation.133

The best proof for a role of p53 in disease progression is derived from a murine model that closely resembles chronic phase CML in which BCR-ABL cDNA regulated by the Tec promoter was introduced.23 Mice expressing BCR-ABL from the Tec promoter were crossed with p53+/− mice. In contrast to BCR-ABL transgenic animals, BCR/ABL-p53+/− animals developed rapid progression to blast crisis.134 This rapid progression of chronic phase to blast crisis was due to loss of function of the remaining p53 allele. Similarly, transplantation of p53-deficient bone marrow cells transduced with BCR-ABL cDNA led to rapid blast crisis.135

In one report, marrow from a CML patient in blast crisis showed a point mutation in the coding region of the p53 gene that was absent in chronic phase CML and upon return to second chronic phase the mutation was undetectable.136 A number of studies using sequential evaluation of bone marrow of patients in chronic phase that evolved to blast crisis have revealed frequent acquisition of p53 mutations.111,112,130,137 Additionally, the blasts of some of these patients displayed decreased apoptosis emphasizing the role of p53-mediated apoptotic cell death that appears to be deficient in blast phase.111

Another tumor suppressor gene p16INK4a located on chromosome 9 has been associated with progression of CML to blast crisis.113,138 P16INK4a is an inhibitor of cyclin D. Cyclin D kinase complexes phosphorylate Rb and prevent cell cycle arrest in G1.139 P16−/− mice are prone to developing cancer and many human tumors carry transcriptionally silent p16 genes due to aberrant methylation of upstream regulatory sequences.140 Sequential studies of CML patients demonstrate homozygous deletions of p16 INK4a acquired in associated with progression to lymphoid blast crisis in approximately 50% cases.113

Alterations in methylation of the proximal promoter of c-ABL appear to be specifically and consistently associated with progression of CML.141,142,143,144 In chronic phase the promoter of ABL is seldom methylated while progressive hypermethylation is observed with late chronic phase, accelerated phase and blast crisis CML. As mentioned above, nuclear p145ABL is important for DNA repair and can induce apoptosis. Thus, silencing of the c-ABL promoter by methylation will further decrease nuclear p145ABL levels, further decreasing apoptosis and perhaps enhancing genomic instability, features that are related to disease progression. Another gene that is hypermethylated during acceleration of CML is the calcitonin gene, although its importance in disease progression is unclear.145

Deletions associated with acquired somatic mutations have been described previously in other leukemias, and small deletions of chromosome 22 sequences adjacent to the Ph chromosome translocation have been identified in CML.146,147 In the past these deletions were thought too small and without pathological significance. Recently, however, sequential analysis of bone marrow of 56 patients with CML revealed that 16 patients had large acquired genomic deletions resulting in loss of chromosome 9 or 22 sequences flanking the translocation breakpoint on the derivative 9, on additional partner chromosomes, or on both.148 These results suggest that the loss of a gene or genes adjacent to the translocation breakpoint may influence the progression of CML.

Other rare forms of genetic or molecular defects such as deletions in the retinoblastoma gene,114 decreased Ikaros activity149 and loss of imprinting150 have been described in progression from chronic phase to blast crisis CML but their contribution to disease progression remains speculative.

Activation of oncogenes

Increased levels of BCR-ABL mRNA and protein are associated with disease progression.92 This can be due to duplication of the Philadelphia chromosome, the most frequent cytogenetic change preceding disease transformation.108,151 In other patients increased levels of BCR-ABL mRNA may represent increased translational activity of the existing BCR-ABL gene. In vitro studies have shown that resistance to STI-571 can be induced by amplification of the BCR-ABL gene or by reduplication.104 This correlates with poor response rates seen in blast crisis as well as loss of response to STI-571 in responding patients.

Activation of oncogenes in addition to the Ph chromosome has been investigated in CML blast crisis. c-MYC appears to play a role in BCR-ABL-mediated transformation30,152,153,154,155 and may mediate its effects either by antagonising the function of p53156,157 or by acting as a co-operative oncogene with the BCR-ABL.154 MYC expression is normal in chronic phase CML but is increased in patients with blast crisis.116,155 Overexpression of c-MYC occurs as a result of increased transcription156 or trisomy 8158 frequently observed during disease progression or stabilization of c-MYC m-RNA due to polyadenylation.117

Additional translocations like t(3;21) have been reported in high frequency in blast crisis.120,159,160,161 This results in the formation of the chimeric AML/EVI-1 fusion protein that blocks differentiation and stimulates proliferation. It can therefore assist the progression of CML through interference with cell growth and differentiation.162 Although RAS plays a central role in the signal transduction activity of BCR-ABL,85,86,163,164,165 the role of RAS mutations in CML blast crisis seems unclear. In one study, only two of 22 samples of patients in blast crisis showed mutations for K-RAS166 and no mutations for N-RAS were detected in another analysis of 121 patients in blast crisis.167 Despite evidence that many oncogenes are involved in the progression of CML, currently there is no single oncogene in addition to BCR-ABL that has been shown to definitively cause this phenomenon.

Impaired DNA repair

Genetic instability due to dysfunction of DNA repair has long been considered a cause of the non-random chromosomal abnormalities that contributes to disease progression. However, not all the studies support the notion of genomic instability in CML.105,168,169 Additionally, whether genomic instability is a cause or effect of disease progression is also not known.170 Although c-ABL has a role in DNA repair after damage34,171 and can interact with DNA repair proteins such as DNA protein kinases (DNA-PKcs),35 how loss of one ABL allele and presence of BCR-ABL affects DNA repair is not understood. In an interesting recent study it was shown in murine and human p210BCR/ABL containing cells that BCR-ABL might down-regulate the DNA repair protein DNA-PKcs.172 These findings suggest that increasing levels of BCR-ABL protein lead to inhibition of DNA repair that can lead to accumulation of other genetic defects and disease progression. It is possible that instability of the genome may be a feature of the CML, which becomes significant at a certain threshold level of BCR-ABL protein or signaling.

Conclusions

In summary, expression of the BCR-ABL oncoprotein leads to an inherently unstable genome in the hematopoeitic stem cell. There is a resultant increase in proliferation, which may increase the likelihood of non-random mutations. Impaired DNA repair contributes to the accumulation of non-random chromosomal abnormalities in addition to BCR-ABL and multiple different cytogenetic and molecular abnormalities are commonly seen with disease progression. Increased p210BCR-ABL protein levels in advanced disease further increases the resistance of the leukemic clone to apoptosis, resulting in tolerance to the genetic errors accumulating in the malignant clone. Subsequent dominance of one or more clones finally leads to culmination in fatal blast crisis. Currently, there is no well-characterized genetic or cellular event that overwhelmingly contributes to disease progression, emphasizing the complexity and redundant nature of the multiple signaling pathways in this disease. The most frequent abnormalities seen are loss of p53 and reduplication of the Ph chromosome, which lead to rapid development of blast crisis. These abnormalities need further characterization to determine their precise role and exact contribution to disease progression.

Ideally, disease progression should be studied in an animal model of chronic phase CML. Despite the existence of many different murine models of CML only one model replicates relatively faithfully the extended chronic phase of CML.23 This model has been successfully used to demonstrate a role of p53 in disease progression.134 However, loss of p53 alone does not fully explain this complicated event and the search for other co-operative genes must continue. Development of better animal models can delineate mechanisms for disease progression and may facilitate development of novel methods that would treat this fatal event.

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  1. Stem Cell Institute and Division of Hematology, Department of Medicine, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA

    AS Shet, BN Jahagirdar & CM Verfaillie

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  1. AS Shet
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  2. BN Jahagirdar
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Shet, A., Jahagirdar, B. & Verfaillie, C. Chronic myelogenous leukemia: mechanisms underlying disease progression. Leukemia 16, 1402–1411 (2002). https://doi.org/10.1038/sj.leu.2402577

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Keywords

  • chronic myelogenous leukemia
  • BCR-ABL
  • blast crisis
  • disease progression
  • mechanisms

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