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April 2002, Volume 16, Number 4, Pages 740-744
Table of contents    Previous  Article  Next   [PDF]
Keynote Address
Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML
K Deguchi1,2 and D G Gilliland1,2

1Howard Hughes Medical Institute, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA

2Harvard Medical School, Boston, MA, USA

Correspondence to: D G Gilliland, Harvard Medical School, 4 Blackfan Circle, Room 418, Boston, MA 02115, USA; Fax: 617 525 5530

This paper is part of a series of keynote addresses to be published in Leukemia. They were presented at the Acute Leukemia Forum, San Francisco, 20 April 2001. Supported by an unrestricted educational grant from Immunex.

Abstract

Leukemia (2002) 16, 740-744. DOI: 10.1038/sj/leu/2402500

Chronic myeloid leukemia (CML) syndromes are characterized by a proliferative and/or survival advantage of myeloid lineage cells, with normal myeloid maturation and differentiation. At least six distinct chromosomal translocations have been associated with this phenotype in humans, of which the most common is the t(9;22) giving rise to BCR/ABL fusion protein. Each of these translocations associated with CML syndromes have been cloned, and invariably result in the expression of a fusion protein that has a carboxy terminal tyrosine kinase domain and an oligomerization motif on the respective amino terminus that serves to oligomerize and constitutively activate the tyrosine kinase. The transforming properties of these kinases have been demonstrated in a broad spectrum of systems, including cultured hematopoietic cell lines and murine models. For example, we have employed a bone marrow transplantation model to study the transforming properties of these fusion proteins in primary hematopoietic cells. The fusion clone is introduced into a murine ecotropic retrovirus with flanking long terminal repeat (LTR) sequences that allow for stable integration and expression of the fusion protein in bone marrow cells. The retroviral constructs are transduced into bone marrow cells from donor mice primed with 5-fluorouracil (5-FU) to bring progenitor cells into cycle and render them susceptible to retroviral transduction. Transduced bone marrow is then reinfused into lethally irradiated syngeneic recipients. When this experiment is performed with any of the fusion proteins associated with chronic myeloid leukemia syndromes in humans, including the BCR/ABL, TEL/ABL, TEL/PDGFbetaR or TEL/JAK2 fusions, respectively, transplanted mice die of leukemia within 50 days. Importantly, this activity is absolutely dependent on tyrosine kinase activity in that point mutations that inactivate the respective tyrosine kinase abrogate the leukemic phenotype.1,2,3,4,5,6,7,8,9,10,11,12,13

Clinically, the mice manifest a disease characterized by leukocytosis with normal maturation of myeloid lineage cells into terminally differentiated neutrophils. As in humans with chronic myeloproliferative disorders, these animals also have myeloid hyperplasia in the bone marrow, and extramedullary hematopoiesis involving myeloid lineage cells in the spleen and to a lesser extent in the liver. Thus, these tyrosine kinase fusion proteins recapitulate the human disease phenotype. In summary, CML syndromes in humans are invariably associated with constitutively activated tyrosine kinases. The tyrosine kinase fusions are sufficient to cause a CML-like disease in a murine bone marrow transplant model and, importantly, CML disease induction in this context is absolutely dependent on tyrosine kinase activity.

These data collectively indicate that tyrosine kinases are validated therapeutic targets for clinical therapeutic intervention. Recently, Druker, Sawyers, and their colleagues at MD Anderson have provided direct evidence that the ABL kinase is a therapeutic target in BCR/ABL-positive CML in humans. They tested the clinical efficacy of a STI571, a 2-phenylaminopyrimidine which selectively binds with high affinity to the ATP binding site of the ABL, PDGFbetaR, and c-KIT tyrosine kinases. STI571 binding to constitutively activated tyrosine kinases containing the ABL or PDGFbetaR fusion proteins inhibits kinase activity by precluding access of ATP and substrates to the active site.1 In this trial, 83 CML patients who failed interferon-alpha therapy were treated. Side-effects were modest and, in fact, the maximum tolerated dose was never reached in this study. Complete hematologic responses were seen in 53 of 54 patients that were treated with doses over 300 mg. Cytogenetic responses occurred in 29 of 54 patients, and there were complete cytogenetic responses in seven of these. Furthermore, STI571 had activity in CML patients who had progressed to myeloid blast crisis, and particularly difficult entity to treat. This impressive response indicates the feasibility of rationale drug design based on an understanding of the genetic basis of human leukemias. We can actually design compounds that target the genes that are responsible for the disease phenotype.

With this background in mind, we can now consider acute myeloid leukemias (AML), which are characterized not only by proliferation and/or survival advantage of leukemic cells, but also by impaired differentiation of those cells. Dozens of chromosomal translocations that are associated with the AML phenotype have been identified and cloned. In contrast to CML, these translocations are almost never associated with tyrosine kinases. Instead, translocations associated with AML almost invariably target transcription factors or components of the transcriptional activation apparatus. These include core binding factor (CBF),14,15,16,17,18,19,20,21,22 retinoic acid receptor alpha,23,24,25,26 HOX family members,27,28,29 transcriptional modulatory proteins, such as MLL,30,31,32,33,34,35,36,37 and transcriptional coactivating proteins, such as CBP, p300, and TIF2.34,37,38,39,40

CBF is a heterodimeric hematopoietic transcription factor that is exemplary of this broad class of translocation associated with AML. It has two subunits, the AML1 subunit and the CBFbeta subunit. CBF transactivates a spectrum of genes that are important for hematopoietic development in both the myeloid and lymphoid lineages, including hematopoietic cytokines and their receptors. Perhaps the most convincing evidence of the importance of CBF in hematopoietic development is that mice engineered to lack both alleles of either AML1 or CBFbeta have an early embryonic lethal phenotype characterized by a complete lack of definitive hematopoiesis.41,42,43,44 Thus, it would be predicted that any translocation, gene rearrangement or point mutation that results in loss of function of either AML1 or CBFbeta would impair hematopoietic differentiation.

As noted above, several chromosomal translocations target CBF. The three most common are the t(8;21), inv(16) and t(12;21) that result in expression of the AML1/ETO, CBFbeta/MYH11 and the TEL/AML1 fusion proteins. The t(8;21) and inv(16) account for about 20-25% of adult AML, whereas the t(12;21) is found in about 20-25% of pediatric acute lymphoblastic leukemia. Not only do these fusion proteins not transactivate normal CBF targets, they are also dominant negative inhibitors of wild-type AML1. Thus, chromosomal translocations that target CBF subunits result in complete loss of function of CBF, and would be expected to impair hematopoietic development. Targeting either AML1/ETO or CBFbeta/MYH11 to their endogenous promoters in murine embryonic stem cells provides strong support for the hypothesis that the fusion proteins cause complete loss of function of CBF. Mice that express AML1/ETO or CBFbeta/MYH11 in the germline have an embryonic lethal phenotype with a lack of definitive hematopoiesis that is nearly identical to mice that have lost both alleles of the AML1 or CBFbeta genes, respectively. Thus, the fusion proteins have a complete dominant negative inhibitory effect on the residual AML1 or CBFbeta allele, respectively. These data indicate that translocations involving CBF in hematopoietic cells would result in impaired differentiation. Recent studies indicate that the dominant inhibitory activity of CBF fusion proteins is due to aberrant recruitment of the nuclear co-repressor complex, including histone deacetylase, to CBF promoters. This observation has prompted experiments to attempt to reverse the block in differentiation induced by CBF fusion proteins using histone deacetylase inhibitors.45,46,47,48

In addition to translocations, we recently determined that inherited leukemia syndromes, such as the familial platelet disorder with propensity to develop acute myelogenous leukemia (FPD/AML) also target the AML1 gene and result in loss of function. The FPD/AML syndrome is autosomal dominant and is characterized by a qualitative and quantitative platelet defect, and by progressive pancytopenia and hematopoietic dysplasia that increases with age in affected individuals. Furthermore, affected individuals progress to AML with acquisition of secondary mutations, with high penetrance over the lifetime of the individual. We performed generalized linkage analysis to identify an FPD/AML locus on chromosome 21 that encompassed the AML1 gene. In six of six FPD/AML pedigrees we analyzed, there was loss of function mutations in the AML1 gene.49 These include deletions, splice acceptor mutations, nonsense mutations that lead to premature truncation of the protein, and missense mutations that result in loss of DNA binding activity. In addition, loss of function point mutations in AML1 also occur in about 3-5% of sporadic cases of AML.50,51 This theme of loss of function of hematopoietic transcription factors as a consequence of point mutations, as well as chromosomal translocations has recently been expanded to include C/EBPalpha, which is required for myeloid differentiation. Loss of function point mutations in C/EBPalpha have recently been reported in AML.52 It seems likely that complete molecular genotyping of AML patients, including cytogenetics and sequence analysis of genes such as AML1 and C/EBPalpha, and, as noted below, N-RAS, K-RAS, FLT3 and c-KIT will be important in determining prognosis, response to therapy, and for the design of rationale therapies targeted to the defective genes.

CBF is thus targeted by chromosomal translocations and point mutations that result in loss of function. However, while CBF mutations and gene rearrangements are necessary for the disease phenotype, a number of lines of evidence suggest that they are not sufficient to cause leukemia. First, in the FPD/AML syndrome, there is a germline loss of function of mutation in AML1, but it takes many years for the patients to develop leukemia, often associated with the acquisition of additional cytogenetic abnormalities, indicating a requirement for a second mutation. Second, murine models of CBF leukemia provide convincing evidence that additional mutations are required.53 Third, and perhaps most convincing, is genetic evidence obtained from the analysis of syngeneic twins who each developed TEL/AML1 positive AML.54,55,56 Greaves and colleagues demonstrated that there had been intrauterine transmission of a single TEL/AML1 clone. Not only did the twins not have leukemia at the time of birth, but they did not develop leukemia until later in life, and at widely disparate times in life. These data strongly support the hypothesis that second mutations are required for the pathogenesis of TEL/AML1-mediated leukemias.

Although these data demonstrate that second mutations are required for CBF-associated AML, they do not provide any clues as to the nature of the second mutations. If CBF mutations are not sufficient to cause leukemia, what is the second genetic event? We can gain important insights into this question from the analysis of disease progression in CML. As noted above, CML syndromes are the consequence of constitutively activated tyrosine kinase. In rare, but highly informative cases of CML disease progression to AML (CML blast crisis), it has been possible to monitor the genetic basis of disease progression. For example, in some cases of BCR/ABL-positive CML, disease progression to AML is associated with acquisition of translocations expressing the AML1/EVI1 or NUP98/HOXA9 fusion proteins.57 TEL/PDGFbetaR associated CMML may progress to AML with acquisition of the t(8;21) that results in the AML1/ETO fusion protein.58 These observations suggest the following testable hypothesis. Proliferative and/or survival advantage for hematopoietic cells is conferred by 'class I' mutations that result in constitutively activated tyrosine kinases, and do not affect differentiation. Alone, these cause a myeloproliferative phenotype, but do not cause AML. 'Class II' mutations, exemplified by core binding factor, result in impaired hematopoietic differentiation, but are not sufficient to cause leukemia. AML is the consequence of cooperation between class I and class II mutations, resulting in proliferative and/or survival advantage of hematopoietic cells and impaired differentiation. Ren and colleagues have obtained experimental evidence in murine models supporting cooperation between BCR/ABL and AML1/EVI1.59 In addition, we have developed a model system that demonstrates cooperativity between the BCR/ABL and NUP98/HOXA9 genes in the development of AML in a murine model. However, as noted above, fusion tyrosine kinases are extremely rare in AML. If the hypothesis is correct, then there must be activating mutations in hematopoietic tyrosine kinases that are not evident by cytogenetic analysis. Therefore, a critical test of the hypothesis of cooperation between class I and class II mutations is the identification of point mutations that constitutively active tyrosine kinases in acute myeloid leukemias.

It has recently been reported that activating mutations in the FLT3 and c-KIT tyrosine kinases meet the criteria for class I mutations in AML.60,61,62,63,64,65,66,67 Approximately 25% of AML patients have internal tandem duplications (ITD) of the juxtamembrane domain of the receptor tyrosine kinase FLT3, and these result in constitutive activation of the FLT3 tyrosine kinase.68,69 In addition, it has been recently reported that activating substitution mutations in the activation loop of the kinase domain at position D835 occur in 7% of patients with AML, and that approximately 5% of AML cases have D816 substitution mutations that result in constitutive activation of c-KIT that confer constitutive activation.

Activated FLT3 transforms hematopoietic cell lines to factor-independent growth, and activated downstream effector pathways, including the STAT5 and RAS/MAPK pathways.68,69 We have recently reported that FLT3/ITD causes a myeloproliferative disorder characterized by leukocytosis with normal maturation of myeloid cells in a murine bone marrow transplantation model, but is not sufficient to cause acute myeloid leukemia.70 These data support the cooperativity model and suggest that FLT3/ITD enhance proliferation of hematopoietic cells, but requires second mutations that impair differentiation to confer a transformed phenotype. It is thus of note that FLT3 activating mutations occur in all subtypes of AML, including core binding factor leukemias and in acute promyelocytic leukemia. Thus, FLT3/ITD may cooperate with, for example, AML1/ETO, CBFbeta/MYH11, or PML/RARalpha to cause AML. This hypothesis can be directly tested in murine models. Furthermore, murine models of FLT3/ITD alone, and in conjunction with other mutations, can be used to test FLT3-specific small molecule inhibitors. The reported activity of STI571 in CML blast crisis provides some hope that FLT3 inhibition may be an effective addition to current therapy for AML. A corollary of these observations is that the remaining cases of AML in which there are not mutations in FLT3 or c-KIT are likely to have activating mutations in other hematopoietic tyrosine kinases or in their downstream effectors. In addition, it is plausible that activation of tyrosine kinases or their effectors will play an important role in pathogenesis of acute lymphoblastic leukemia, chronic lymphocytic leukemia, and in solid tumors.

In summary, our understanding of the genetics of human leukemia has provided the tools that we require to develop rationally designed targeted molecular therapies. The available evidence indicates that AML is the consequence of collaboration between at least two broad classes of mutations. Class I mutations confer a proliferative and/or survival advantage without affecting differentiation, whereas class II mutations serve primarily to impair hematopoietic differentiation. We have proof-of-principle that each of these classes of mutations can be targeted with small molecules. Examples include specific inhibition of BCR/ABL by STI571 in treatment of CML and CML blast crisis, and induction of differentiation in promyelocytic leukemias by use of all-trans retinoic acid to override the dominant negative block in differentiation induced by the PML/RARalpha fusion proteins. The combination of continued discovery and characterization of AML disease alleles with design, development and clinical testing of targeted therapies provides real hope for improved outcome in AML, and perhaps in other hematologic malignancies and solid tumors.

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Received 3 January 2002; accepted 25 January 2002
April 2002, Volume 16, Number 4, Pages 740-744
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