Leukemia Research 26 (2002) 713720

Millennium Review

BcrAbl variants: biological and clinical aspects

Anjali S. Advani a , Ann Marie Pendergast b,
a

Departments of Hematology and Oncology, Duke University Medical Center, Durham, NC 27710, USA b Department of Pharmacology and Cancer Biology, LSRC Room C233A, La Salle St. Extension, Duke University Medical Center, Durham, NC 27710, USA Received 8 November 2001; accepted 25 November 2001

Abstract BcrAbl is an oncogene that arises from fusion of the Bcr gene with the c-Abl proto-oncogene. Three different BcrAbl variants can be formed, depending on the amount of Bcr gene included: p185, p210, and p230. The three variants are associated with distinct types of human leukemias. Examination of the signaling pathways differentially regulated by the BcrAbl proteins will help us gain better insight into BcrAbl mediated leukemogenesis. 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Philadelphia chromosome; BcrAbl; Acute lymphocytic leukemia; Chronic myelogenous leukemia; Chronic neutrophilic leukemia

1. Introduction The Philadelphia chromosome (Ph) involves fusion of the breakpoint cluster region (Bcr) gene on chromosome 22 at band q11 with the Abl proto-oncogene on chromosome 9 at band q34 [1]. Three different forms of the BcrAbl oncogene exist, p185, p210, and p230, that are associated with distinct types of leukemia. P185 is associated with 2030% of acute lymphocytic leukemia (ALL), p210 with 90% of chronic myelogenous leukemia (CML), and p230 with a subset of patients with chronic neutrophilic leukemia (CNL) [2]. This review will discuss the biological and clinical aspects of the BcrAbl variants.

2. Clinical correlates CML typically has a biphasic course that is characterized by chronic and blastic phases [36]. The chronic phase is characterized by an expansion of myeloid cells in the peripheral blood, bone marrow, and spleen. The molecular basis for the myeloid expansion is puzzling as BcrAbl transforms the hematopoietic stem cell and is present in all hematopoietic elements [36]. Approximately 50% of patients in the chronic phase have no symptoms and are diagnosed by routine testing [7,8]. Signs and symptoms, however, can include fatigue, weight loss, abdominal fullness, bleeding, sweats, splenomegaly, and hepatomegaly [79]. The blastic phase is thought to occur secondary to additional mutations (see below). Prior to entering blast phase, 75% of patients develop an intervening accelerated phase that is characterized by increased basophilia, blasts, and promyelocytes [7,10]. This usually progresses to blastic phase within 318 months [7]. The acute leukemia is ALL in one-third of cases, whereas two-thirds are acute undifferentiated leukemia (AUL) or acute myelogenous leukemia (AML) [7,11]. Patients with a lymphoid blastic phase may respond to treatment with ALL regimens; however, the median duration of response is 912 months [7,12]. Because the disease is relatively treatment resistant, the median survival is 3 months for myeloid blast crisis and 6 months for lymphoid blast crisis [1316]. Philadelphia chromosome positive (Ph+) ALL is an acute leukemia, which unlike CML, requires prompt, aggressive

Abbreviations: Ph, Philadelphia chromosome; Bcr, breakpoint cluster region; ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia; CNL, chronic neutrophilic leukemia; AUL, acute undifferentiated leukemia; AML, acute myelogenous leukemia; Ph+, Philadelphia chromosome positive; CALGB, cancer and leukemia group B; BMT, bone marrow transplant; CML-N, cases of chronic neutrophilic leukemia that are Ph+; CMML, chronic myelomonocytic leukemia; RT-PCR, reverse transcriptase polymerase chain reaction; CFU-erythroid, colony forming unit-erythroid; CFU-GM, colony forming unit-granulocyte macrophage; PCR, polymerase chain reaction; STI-571, signal transduction inhibitor 571; ATP, adenosine triphosphate; mRNA, messenger RNA Corresponding author. Fax: +1-919-681-7148. E-mail address: pende014@mc.duke.edu (A.M. Pendergast).

0145-2126/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 1 ) 0 0 1 9 7 - 7

714

A.S. Advani, A.M. Pendergast / Leukemia Research 26 (2002) 713720

treatment with high dose chemotherapy [17]. Compared to BcrAbl negative ALL, it tends to have a worse prognosis. In a Cancer and Leukemia Group B (CALGB) study, the median remission duration for Ph+ ALL was only 8 months [17,18]. Because fewer than 5% of patients are cured by chemotherapy, allogeneic BMT remains the best chance of cure [19,20]. The reason why p185 tends to be associated with acute leukemia is unknown. One hypothesis is that p185 is more efcient at promoting secondary events necessary for the acute phase disease [21]. Although the majority of Ph+ ALL exhibit a B-lymphoid lineage phenotype, Ph+ ALL may also involve the stem cell, because some are biphenotypic [21,22]. In addition, involvement of the myeloid lineage can be seen in both p185 and p210 ALL [2129]. Finally, p230 is associated with a subset of CNL, which has a much more benign course. BcrAbl positive CNL was identied in patients who showed the presence of a BcrAbl e19a2 transcript [30,31]. About 100 cases of BcrAbl positive CNL have been reported [30,32,33]. Most cases of CNL are Ph chromosome negative, so these cases have been referred to as CML-N [30]. CNL involves a sustained mature neutrophilic expansion with mild hepatosplenomegaly. In general, there is a low proportion of immature granulocytes and milder anemia [34]. Progression to blast crisis is uncommon [30]. Although p185 is typically associated with ALL, p230 with CNL, and p210 with CML, there is overlap. P210 occurs in 40% of Ph+ ALL, p185 occurs in 23% CML, and p230 in some cases of CML [2]. Patients with p185 CML are thought to have a disease more reminiscent of chronic myelomonocytic leukemia (CMML), and to have a monocytic defect [2,35]. Kantajaran et al. examined 32 patients with p210 or p185 Ph+ ALL and found no difference in clinico-laboratory, karyotypic, or prognostic implications [13,36]. It is not clear whether intrinisic differences in the activities of the three BcrAbl proteins account for their association with different disease phenotypes or whether

expression of each protein occurs in a distinict hematopoietic lineage. In addition, some patients with CML co-express p185 and p210, based on detection by reverse transcriptase polymerase chain reaction (RT-PCR) [2,3739]. High levels of both transcripts have been found in patients with blastic transformation of CML, whereas those with CML in chronic phase being treated with interferon have low or undetectable levels of p185 [38,39]. This suggests that a quantitative variation of the two transcripts may play a role in the clinical disease [38]. Different forms of p210 are also produced by alternative splicing, namely, b2a2 and b3a2, with the latter encoding a longer transcript. There is some data indicating that patients with b3a2 have a better prognosis than b2a2, exhibiting a long chronic phase and better response to interferon [2,4042]. This is interesting, given that the longer BcrAbl variants (i.e. p230) tend to have a more indolent biological/clinical phenotype than the shorter variants (i.e. p185). However, more recent prospective studies suggest no difference in prognosis between patients with b2a2 versus b3a2 transcripts [4345]. Other data suggest that patients with b3a2 transcripts have higher platelets than patients with b2a2 transcripts [46,47]. Relevant to this, 9/10 patients with Ph+ essential thrombocythemia were found to have the b3a2 variant [4850].

3. An overview: BcrAbl structure and signaling The BcrAbl fusion protein acts as an onco-protein by activating several signaling paths that lead to transformation. Among these are Myc, Ras, c-Raf, MAPK/ERK, SAPK/JNK, Stat, NFKB, PI-3 kinase, and c-Jun [5161]. Inhibition of Ras [62], Raf [63], PI3K [64], Akt [65], Jun [66,67], and Myc [68,69] impairs BcrAbl mediated transformation. The oncogenic ability of BcrAbl requires deregulated tyrosine kinase activity which leads to recruit-

Fig. 1. Structural features of the BcrAbl variants. The p185 BcrAbl protein is primarily associated with ALL, p210 BcrAbl with CML, and p230 BcrAbl with CNL. The C-terminal (Abl) region of all BcrAbl variants contains Src-homology (SH3 and SH2) domains, tyrosine kinase (SH1) domain, proline-rich sequences that contain PXXP motifs for SH3 domain binding, DNA binding domain, actin binding domain, nuclear localization signals (NLS), and nuclear export signal (NES). The N-terminal (Bcr) portion of the protein differs among the variants. The variants include different amounts of Bcr sequence, with p230 including the largest amount of Bcr sequence. All three variants have a dimerization domain (DD) and serine/threonine kinase domain (P-S/T). P210 and p230 both have Dbl and PH domains. In addition, p230 has a calcium/phospholipid binding domain (CalB) and a GapRac domain.

A.S. Advani, A.M. Pendergast / Leukemia Research 26 (2002) 713720

715

ment of adaptor molecules, phosphorylation of signaling molecules, and activation of downstream signaling events [7073]. Structurally, BcrAbl contains multiple domains (Fig. 1). The Abl sequences encode Src-homology (SH3 and SH2) domains, tyrosine kinase domain, DNA-binding domain, actin-binding domain, nuclear localization signals, and nuclear export signal [3,74]. The Bcr region contains a coiled-coil oligomerization domain, serine/threonine kinase domain, pleckstrin homology (PH) domain, a Dbl/cdc24 guanine nucleotide exchange factor homology domain, several serine/threonine and tyrosine phosphorylation sites, and binding sites for the Abl SH2 domain, Grb2, and 14-3-3 proteins [3,75,76]. The SH2 domain of BcrAbl recruits signaling proteins such as p62dok, c-Cbl, and Rin1 [3,7785]. Binding and phosphorylation of these molecules may be functionally important as SH2 mutations in BcrAbl affect the course of disease in biological models [85]. The actin binding domain directly links BcrAbl to the cytoskeleton, and facilitates tyrosine phosphorylation of cytoskeletal proteins [86]. Expression of the BcrAbl kinases upregulates cell proliferation [68,69,8791], decreases apoptosis [87,9294], increases cytokine-independent growth [4,95,96], decreases adhesion to the bone marrow stroma [4,87], and produces cytoskeletal abnormalities [4,87].

4. BcrAbl variants: molecular structure BcrAbl oncogenes differ in the amount of Bcr included in the fusion protein, and are formed by joining of various amounts of the Bcr gene to the same Abl sequences. This difference in structure inuences the biological and clinical phenotypes associated with the BcrAbl variants [2]. Splicing at the m, M, or breakpoints in Bcr produces three distinct protein products, namely, p185 (e1a2 junction), p210 (b2a2 or b3a2 junction), and p230 (e19a2 junction) (Fig. 1) [2,97]. P185 encodes the dimerization and SH2- binding domains of Bcr [98,99]. P210 has in addition to the domains present in p185, the Bcr PH and Dbl domains [43,100]. Finally, P230 has the largest amount of Bcr sequence, including the calcium/phospholipid binding domain and the rst third of the domain associated with GTPase activity for p21 (GAPRac) [30]. The inclusion of the Dbl/PH domains in p210 and p230 may contribute to the granulocytic differentiation associated with these variants.

5. BcrAbl proteins: biological/laboratory correlates Although the three BcrAbl kinases (p185, p210, and p230) are similar in structure, they exhibit distinct properties. When primary mouse bone marrow cells are infected with the different BcrAbl variants, and cultured in the

presence of cytokines and stroma, p185 cultures differentiate into a lymphoid lineage, whereas p210 and p230 become myeloid [100]. In vitro, p185 has increased ability to stimulate expansion of lymphoid cells, compared to p210 [101]. P230 BcrAbl cultures require cytokines for optimal growth, whereas p185 and p210 BcrAbl cultures are cytokine-independent for growth and survival [100]. P185 BcrAbl has a greater tumorigenic potential than p210 or p230 BcrAbl [100,102]. In soft agar assays, p185 is 100-fold more effective than p210 at eliciting transformation [73]. It was reported that SCID mice injected with p185-expressing primary bone marrow cells developed pre-B cell tumors, whereas no tumors developed in mice injected with p210- or p230-expressing cells [100]. Miller and Pear have also shown a less aggressive leukemia associated with p230 BcrAbl in 5 FU-lethally irradiated mice [100]. All mice injected with the three BcrAbl variants developed a myeloproliferative disease, but there was an increased latency in p230- injected mice (27 weeks) versus 45 weeks in the p185- and p210-injected mice [100]. There are several possibilities to explain the different biological effects of the three BcrAbl kinases. Li et al. have shown that p230 exhibits lower intrinsic tyrosine activity than p185 and p210 [102]. P210 also has been shown to have decreased tyrosine kinase activity than p185 [73]. In addition, Nishimura et al. have shown that different sets of tyrosine phosphorylated proteins may exist in p185 versus p210 leukemic cell lines [103]. A 36 kDa protein was detected in K562 cells (p210 cell line), but not MR87 (p185 cell line); and a 62 kDa protein was present in MR87 but not in K562 [103]. The 62 kDa protein was a Gap-like protein, and is a cytoskeletal target for tyrosine kinases [103]. Hef1, a member of the 1 integrin signaling pathway, is tyrosine phosphorylated in p185, but not p210 [104]. Tyrosine phosphorylation of these proteins, may lead to differential interaction with the cytoskeleton or altered downstream signaling. Although Stat5, Stat1, and Stat3 are constitutively activated by tyrosine phosphorylation in p185- and p210-expressing cells, p185 but not p210 promotes activation of Stat6 [59]. Additionally, it was recently demonstrated that the SH2 domain is required for efcient induction of CML-like disease in mice by p210, but not p185, further suggesting a difference in signaling between the two variants [85]. It is possible that differences in the content of the Bcr region itself may lead to distinct clinical disease [105]. Additional Bcr sequences, such as Dbl/PH in p210 and GapRac in p230 may allow for increased differentiation along the myeloid lineage [2,105,106]. The Dbl/PH domains present in p210 but not p185, may also contribute to the stabilization of actin bers [107,108]. Dbl is known to activate Rho, and activated Rho promotes the formation of actin stress bers [109,110]. It has been reported that a BcrAbl fusion containing Bcr (amino acids 1191) can efciently transform rat 1-myc cells, but fusion of additional Bcr sequences present in p210 causes decreased disorganization of the actin cytoskeleton [107]. Alternatively, it is

716

A.S. Advani, A.M. Pendergast / Leukemia Research 26 (2002) 713720

possible that Bcr breakpoints that yield p185 may occur preferentially in immature B cells, and breakpoints that produce p210, in hematopoietic stem cells [105]. The latter point is supported by data from Li et al. [102]. In a murine bone marrow transplantation model, p185, p210, and p230 were all equally potent in inducing a CML-like disease, when 5 FU donors were used. The proviral integration site was polyclonal, implicating a multipotential target cell [102]. When no 5 FU was used, a mixture of CML, ALL, and macrophage tumors was observed [102]. P185 in these mice induced lymphoid leukemias with a shorter latency than p210 or p230. In addition, lymphoid leukemias were oligoclonal, suggesting a lineage restricted target cell [102]. This data, however, has not been supported by analysis of patients with Ph+ ALL. Adult patients with Ph+ ALL have been reported to have a multipotential stem cell target based on examination of metaphases of individual colony forming unit-erythroid (CFU-erythroid) and CFU-granulocyte macrophage (CFU-GM) [29,111,112]. This suggests there may differences in the biology of BcrAbl in patients versus animal models.

6. Molecular changes: blastic phase of CML CML eventually progresses to a blastic phase, reminiscent of acute leukemia that is much more treatment resistant [13,113]. The molecular changes that accompany this event have been of interest, but are not consistent. Progression to blast crisis has been shown to correlate with the addition of cytogenetic abnormalities such as 22q, loss of the Y chromosome, isochromosome 17, trisomies-8, -9, -19, an additional Ph chromosome, translocation t(3;21), or inversion of chromosome 16 [13,114,115]. Specic mutations have been observed in Ras, p53, Myc, p16, and Rb [116121]. In addition, increased transcription of BcrAbl, h-Ras, and c-Myc is detected in many clinical cases of accelerated phase CML [122130]. In some cases, alterations in known oncogenes/tumor suppressers correspond to the cytogenetic changes seen above. For example, p53 is located on chromosome 17, Rb on chromosome 13, c-Myc on chromosome 8, p16 on chromosome 9, and AML/EV-1 on chromosomes 3 and 21 [127]. In addition, AXL, a putative receptor with tyrosine kinase activity, located on chromosome 19, may be involved in the progression of CML to blastic phase [21,128130].

7. Current treatment implications Traditionally, CML in the chronic phase has been treated with a combination of hydroxyurea and interferon, with a 73% hematologic response rate and 58% rate of cytogenetic remissions [13,131,132]. This has been slightly improved with the addition of cytarabine [13]. Despite this, the 5 year survival rates are 57% [131,132], so allogeneic bone

marrow transplant (BMT) has been the treatment of choice for younger patients with an HLA matched identical sibling, showing a 70% cure rate [13,133]. However, only a minority of patients are transplanted because of age, or lack of an HLA-matched identical sibling [13]. After transplant, PCR for BcrAbl has been used to monitor patients disease status. Repeated PCR positivity at greater than 6 months post-transplant or increasing values based on quantitative PCR tend to correlate with relapse [13,134,135]. Donor lymphocyte infusions have been found to be the most effective form of adoptive salvage immunotherapy in patients who relapse post-transplant [7,136]. Other treatments for CML have been investigated including antisense oligonucleotides, immunotherapy, farnesyl transferase inhibitors, and tyrosine kinase inhibitors [87]. The tyrosine kinase inhibitors have been of particular interest because numerous studies have demonstrated that tyrosine kinase activity is required for the transforming capacity of BcrAbl [73,87,137]. In the mid-1990s, signal transduction inhibitor 571 (STI-571) (Gleevec), a phenylaminopyrimide derivative with potent tyrosine kinase inhibition and selectivity for Abl, c-Kit, and platelet-derived growth factor was developed [87,138]. STI-571 binds to a pocket of the catalytic domain of the Abl tyrosine kinase and competitively inhibits binding of adenosine triphosphate (ATP), thereby resulting in inhibition of autophosphorylation and inhibition of substrate phosphorylation [139]. Pre-clinically, it was shown that STI-571 caused a dose-dependent inhibition of 32D 210 cells injected into mice [140]. Subsequently, a phase 1 trial was carried out with 54 patients with CML refractory to interferon- . Of these patients, 23/24 patients receiving a dose of 300 mg or higher underwent a complete hematologic remission, and 8/24 had a complete cytogenetic remission [141]. Currently, a phase 3 study is underway comparing STI-571 versus interferon- +/ cytarabine as front-line therapy for CML [87]. STI-571 was also used in 33 patients with Ph+ acute leukemia. Both blast crisis and Ph+ ALL are difcult to treat. Patients with a myeloid blast crisis treated with STI-571 had a 55% response rate and 22% complete remission rate. Patients with lymphoid blast crisis had an 82% response rate and 55% complete remission rate [142]. These results are surprisingly encouraging, and suggest that either the BcrAbl tyrosine kinase activity is necessary for blastic transformation of that other signaling pathways that are activated during blast phase are inhibited by STI-571 [143]. Despite enthusiasm based on the above results, the emergence of STI-571 resistance in patients with acute leukemia, and the isolation of Ph+ leukemia cell lines that are resistant to STI-571 highlights the need for combination therapy [144,145]. The molecular mechanism of resistance includes increased BcrAbl messenger RNA (mRNA), increased protein, amplication of the transgene, and point mutations within the Abl kinase domain of BcrAbl [144146]. Currently, trials with ST-571 combined with chemotherapy for

A.S. Advani, A.M. Pendergast / Leukemia Research 26 (2002) 713720

717

Ph+ leukemias are underway. In addition, other molecular targeted therapies are being examined. Second generation tyrosine kinase inhibitors are being developed for testing [87]. An alternative approach to inhibition of the kinase has been to develop an Abl-targeted tyrosine phosphatase [147]. Because Ras activation is thought to be important in BcrAbl mediated transformation, farnesyl transferase inhibitors have also been of particular interest [148]. The farnesyl transferase inhibitor, SCHH66336 has been designed to block both mutant and wild-type Ras signaling in transformed cells [148]. In a murine ALL model, it has been shown to revert early signs of leukemia and signicantly prolong survival [148]. Currently, it is being investigated in clinical trials. The above therapies are illustrative of how understanding the molecular biology of a disease can contribute to elegant and successful molecular targeted therapies. It is likely this paradigm will be applied to other diseases.

Acknowledgements A.S. Advani is supported by National Institutes of Health Training Grant 2-T32-HC07057-26. A.M. Pendergast is supported by National Institutes of Health grants CA61033 and CA70940. References
[1] Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukemia identied by quinacrine uorescence and Giesma staining. Nature 1973;243:290. [2] Melo JV. The diversity of BCRABL fusion proteins and their relationship to leukemia phenotype. Blood 1996;88:2375. [3] Zhang X, Rong R, Hao SX, Pear WS, Ren R. The SH2 domain of BcrAbl is not required to induce a murine myeloproliferative disease; however, SH2 signaling inuences disease latency and phenotype. Blood 2001;97:277. [4] Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999; 340:1330. [5] Goldman JM. Chronic myeloid leukemia. Curr Opin Hematol 1997;4:277. [6] Faderl S, Talpaz M, Estrov Z, OBrien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164. [7] Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology 1999;13:169. [8] Kantarjian HM, Deisseroth A, Kurzrock R, et al. Chronic myelogenous leukemia: a concise update. Blood 1993;82:691. [9] Cortes J, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. Am J Med 1996;100:555. [10] Kantarjian H, Dixon D, Keating MJ, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer 1988;61:1441. [11] Grifn JD, Todd III RF, Ritz J, et al. Differentiation patterns in the blastic phase of chronic myeloid leukemia. Blood 1983;61:85. [12] Kantarjian HM, Keating MJ, Talpaz M, et al. Chronic myelogenous leukemia in blast crisis: analysis of 242 patients. Am J Med 1987;83:445. [13] Thijsen S, Schuurhuis G, van Oostveen J, Ossenkoppele G. Chronic myeloid leukemia from basics to bedside. Leukemia 1999;13:1646.

[14] Derderian PM, Kantarjian HM, Talpaz M, OBrien S, Cork A, Estey E, et al. Chronic myelogenous leukemia in the lymphoid blastic phase: characteristics, treatment response, and prognosis. Am J Med 1993;94:69. [15] Kantarjian HM, Talpaz M, Kontoyiannis D, Gutterman J, Keating MJ, Estey EH, et al. Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 1992;10:398. [16] Kantarjian HM, Walters RS, Keating MJ, Talpaz M, Andersson B, Beran M, et al. Treatment of the blastic phase of chronic myelogenous leukemia with mitoxantrone and high-dose cytosine arabinoside. Cancer 1988;62:672. [17] Hoelzer D. Therapy and prognostic factors in adult acute lymphoblastic leukemia. Baillieres Clin Haematol 1994;7:299. [18] Hooberman A, Westbrook C, Spino C, et al. Clinical signicance of molecular detection of the BCRABL fusion gene in acute lymphoblastic leukemia (ALL): a Cancer and Leukemia Group B (CALGB) study. Proc Am Soc Clin Oncol 1991;10:222. [19] Spencer A, OBrien SG, Goldman JM. Options for therapy in chronic myeloid leukaemia. Br J Haematol 1995;91:2. [20] Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med 1998;339:605. [21] Allen PB, Morgan GJ, Wiedemann LM. Philadelphia chromosomepositive leukemia: the translocated genes and their gene products. Baillieres Clin Haematol 1992;5:897. [22] Reardon DA, Hanson CA, Roth MS, Castle VP. Lineage switch in Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 1994;73:1526. [23] Abe R, Ishibashi T, Kimura H, et al. The signicance of cytogenetic ndings of erythroid colonies derived from a Ph+ ALL patient: fundamental differences between Ph+ ALL and blastic CML. Cancer Genet Cytogenet 1985;18:49. [24] Kitano K, Sato Y, Suda T, Miura Y. Difference of cell lineage expression of hematopoietic progenitor cells in Philadelphia-positive acute lymphoblastic leukemia and chronic myelogenous leukemia. Br J Haematol 1988;70:21. [25] Secker-Walker LM, Cooke HMG, Browett PJ, et al. Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 1988;72:784. [26] Turhan AG, Eaves CJ, Kalousek DK, et al. Molecular analysis of clonality and bcr rearrangements in Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1988;71: 1495. [27] Craig JM, Hawkins JM, Yamada T. First intron and M-bcr breakpoints are restricted to the lymphoid lineage in Philadelphia positive acute lymphoblastic leukemia. Leukemia 1990;4:678. [28] Dow LW, Tachibana N, Raimondi SC, Lauer SJ, Witte ON, Clark SS. Comparative biochemical and cytogenetic studies of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and other 22q11 variants. Blood 1989;73:1291. [29] Tachibana N, Raimondi SC, Lauer SJ, et al. Evidence for a multipotential stem cell in some childhood Philadelphia chromosomepositive acute lymphoblastic leukemias. Blood 1987;70: 1458. [30] Pane F, Frigeri F, Sindona M, Luciano L, Ferrara F, Cimino R, et al. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specic molecular marker BCR/ABL with C3/A2 junction. Blood 1996;88:2410. [31] Tuohy EL. A case of splenomegaly with polymorphonuclear neutrophil hyperleukocytosis. Am J Med Sci 1920;18:160. [32] Meyer S, Feremans W, Cantiniaux B, Capel P, Huygen R, Dicato M. Successful alpha-2b-interferon therapy for chronic neutrophilic leukemia (letter). Blood 1993;82:1035. [33] Kwong YL, Cheng G. Clonal nature of chronic neutrophilic leukemia (letter). Blood 1993;82:1035. [34] Melo JV. BcrAbl gene variants. Baillieres Clin Haematol 1997; 10:203.

718

A.S. Advani, A.M. Pendergast / Leukemia Research 26 (2002) 713720 [53] Cortez D, Kadlec L, Pendergast AM. Structural and signaling requirements for BCRABL-mediated transformation and inhibition of apoptosis. Mol Cell Biol 1995;15:5531. [54] Salomoni P, Wasik MA, Riedel RF, Reiss K, Choi JK, Skorski T, et al. Expression of constitutively active Raf-1 in the mitochondria restores antiapoptotic and leukemogenic potential of a transformation-decient BCR/ABL mutant. J Exp Med 1998; 187:1995. [55] Okuda K, Matulonis U, Salgia R, Kanakura Y, Druker B, Grifn JD. Factor independence of human myeloid leukemia cell lines is associated with increased phosphorylation of the proto-oncogene Raf-1. Exp Hematol 1994;22:1111. [56] Burgess GS, Williamson EA, Cripe LD, Litz-Jackson S, Bhatt JA, Stanley K, et al. Regulation of the c-jun gene in p210 BCRABL transformed cells corresponds with activity of JNK, the c-jun N-terminal kinase. Blood 1998;92:2450. [57] Sawyers CL, Callahan W, Witte ON. Dominant negative MYC blocks transformation by ABL oncogenes. Cell 1992;70:901. [58] Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL. Constitutive activation of STAT5 by the BCRABL oncogene in chronic myelogenous leukemia. Oncogene 1996;13:247. [59] Ilaria Jr RL, Van Etten RA. P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specic STAT family members. J Biol Chem 1996;271:31704. [60] Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 1997;16:6151. [61] Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin Jr AS. A requirement for NF-kappaB activation in BcrAbl-mediated transformation. Genes Dev 1998;12:968. [62] Sawyers CL, McLaughlin J, Witte ON. Genetic requirement for Ras in the transformation of broblasts and hematopoietic cells by the BcrAbl oncogene. J Exp Med 1995;181:307. [63] Okuda K, Matulonis U, Salgia R, Kanakura Y, Druker B, Grifn JD. Factor independence of human myeloid leukemia cells is associated with increased phosphorylation of the proto-oncogene Raf-1. Exp Hematol 1994;22:1111. [64] Skorski T, Kanakaraj P, Nieborowska-Skorska M, et al. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood 1995;86:726. [65] Skorski T, Bellacosa A, Nieborowska-Skorska M, et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3K/Akt-dependent pathway. EMBO J 1997;16: 6151. [66] Raitano AB, Halpern JR, Hambuch TM, Sawyers CL. The BcrAbl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc Natl Acad Sci USA 1995;92:11746. [67] Dickens M, Rogers JS, Cavanaugh J, et al. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science 1997;277:693. [68] Sawyers CL, Callahan W, Witte ON. Dominant negative Myc blocks transformation by ABL oncogenes. Cell 1992;70:90110. [69] Afar DEH, Goga A, McLaughlin J, Witte ON, Sawyers CL. Differential complementation of BcrAbl point mutants with c-Myc. Science 1994;264:424. [70] Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW, et al. Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway. Genes Dev 1998;12:1415. [71] Evans CA, Owen-Lynch PJ, Whetton AD, Dive C. Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hemopoietic cells. Cancer Re 1993;53:1735. [72] Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990;247:824.

[35] Melo JV, Myint H, Galton DA, Goldman JM. P190 BCRABL chronic myeloid leukemia: the missing link with chronic myelomonocytic leukemia? Leukemia 1994;8:208. [36] Kantarjian HM, Talpaz M, Dhingra K, Estey E, Keating MJ, Ku S, et al. Signicance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia. Blood 1991;78:2411. [37] Saglio G, Pane F, Gottardi E, Frigeri F, Buonaiuto MR, Guerasio A, et al. Consistent amounts of acute leukemia-associated P190 BCR/ABL transcripts are expressed by chronic myelogenous leukemia pateints at diagnosis. Blood 1996;87:1075. [38] Saglio G, Pane F, Martinelli G, Guerrasio A. BCR/ABL rearrangement and leukemia phenotype. Leukemia 1999;13(Suppl 1):S96. [39] van Rhee F, Hochhaus A, Lin F, Melo JV, Goldman JM, Cross NCP. P190 BCRABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. Blood 1996;87:5213. [40] Mills KI, MacKenzie ED, Birnie GD. The site of the breakpoint within the bcr is a prognostic factor in Philadelphia-positive CML patients. Blood 1988;72:1237. [41] Mills KI, Sproul AM, Leibowitz D, Burnett AK. Mapping of breakpoints, and relationship to BCRABL RNA expression, in Philadelphia-chromosome-positive chronic myeloid leukemia patients with a breakpoint around exon 14 (b3) of the BCR gene. Leukemia 1991;5:937. [42] Elliott SL, Taylor KM, Taylor DL, Rodwell RL, Williams BF, Shuttlewood MM, et al. Cytogenetic response to alpha-interferon is predicted in early chronic phase chronic myeloid leukemia by M-bcr breakpoint location. Leukemia 1995;9:946. [43] Shepherd P, Suffolk R, Halsey J, Allan N. Analysis of molecular breakpoint and m-RNA transcripts in a prospective randomized trial of interferon in chronic myeloid leukemia: no correlation with clinical features, cytogenetic response, duration of chronic phase, or survival. Br J Haematol 1995;89:546. [44] Fioretos T, Nilsson PG, Aman P, Heim S, Kirstoffersson U, Malm C, et al. Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia. Leukemia 1993;7:1225. [45] Rozman C, Urbano Ispizua A, Cervantes F, Rozman M, Colomer D, Feliz P, et al. Analysis of the clinical relevance of the breakpoint location within M-bcr and the type of chimeric mRNA in chronic myelogenous leukemia. Leukemia 1995;9:1104. [46] Inokuchi K, Inoue T, Tojo A, Futaki M, Miyake K, Yamada T, et al. A possible correlation between the type of bcrabl hybrid messenger RNA and platelet count in Philadelphia-positive chronic myelogenous leukemia. Blood 1991;78:3125. [47] Ardern JC, Speak J, Hyde K, Hunt LP, Lawson R, Gorst DW, et al. Molecular analysis in chronic granulocytic leukemia: location of breakpoints within M-bcr and relationship with presentation platelet counts. Clin Lab Hematol 1993;15:253. [48] Martiat P, Ifrah N, Rassool F, Morgan G, Giles F, Gow J, et al. Molecular analysis of Philadelphia positive essential thrombocythemia. Leukemia 1989;3:563. [49] Cervantes F, Urbano Ispizua A, Villamor N, Feliu E, Milla F, Lopez Guillermo A, et al. Ph-positive chronic myeloid leukemia mimicking essential thrombocythemia and termination into megakaryoblastic blast crisis: report of two cases with molecular studies. Leukemia 1993;7:327. [50] Morris CM, Heisterkamp N, Groffen J, Fitzgerald PH. Entire ABL gene is joined with 5 -BCR in some patients with Philadelphia-positive leukemia. Blood 1991;78:1078. [51] Cortez D, Reuther G, Pendergast AM. The BcrAbl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells. Oncogene 1997;15:2333. [52] Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, et al. BCRABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell 1993;75:175.

A.S. Advani, A.M. Pendergast / Leukemia Research 26 (2002) 713720 [73] Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcrabl oncogene products. Science 1990;247:1079. [74] Wang JY. Abl tyrosine kinase in signal transduction and cell-cycle regulation. Curr Opin Genet Dev 1993;3:35. [75] Raitano AB, Whang YE, Sawyers CL. Signal transduction by wild-type and leukemogenic Abl proteins. Biochim Biophys Acta 1997;1333:F201. [76] Ghaffari S, Daley GQ, Lodish HF. Growth factor independence and BCR/ABL transformation: promise and pitfalls of murine model systems and assays. Leukemia 1999;13:1200. [77] Pendergast AM, Muller AJ, Havlik MH, Maru Y, Witte ON. BCR sequences essential for transformation by the BCRABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner. Cell 1991;66:161. [78] Howell BW, Gertler FB, Cooper JA. Mouse disabled (mDab1): a Src binding protein in neuronal development. EMBO J 1997;16:121. [79] Yamanashi Y, Baltimore D. Identication of the Abl- and rasGAP-associated 62 kDa protein as a docking protein. Dok Cell 1997;88:205. [80] Carpino N, Wisniewski D, Strife A, et al. P62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell 1997;88:197. [81] Bhat A, Johnson KJ, Oda T, Corbin AS, Druker BJ. Interactions of p62(dok) with p210(bcrabl) and BcrAbl associated proteins. J Biol Chem 1998;273:32360. [82] Bhat A, Kolibaba K, Oda T, Ohno-Jones S, Heaney C, Druker BJ. Interactions of CBL with BCRABL and CRKL in BCRABLtransformed myeloid cells. J Biol Chem 1997;272:16170. [83] Afar DE, Han L, McLaughlin J, et al. Regulation of the oncogenic activity of BCRABL by a tightly bound substrate protein RIN1. Immunity 1997;6:773. [84] Kapeller R, Moriarty A, Strauss A, et al. Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin. J Biol Chem 1999;274:24980. [85] Roumiantsev S, de Aos IE, Varticovski L, Ilaria R, Van Etten RA. The src homology 2 domain of Bcr/Abl is required for efcient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase. Blood 2001;97:4. [86] Heisterkamp N, Voncken JW, Senadheera D, Gonzalez-Gomez I, Reichert A, Haataja L, et al. Reduced oncogenicity of p190 Bcr/Abl F-actin-binding domain mutants. Blood 2000;96:2226. [87] Jahagirdar BN, Miller JS, Shet A, Verfaillie CM. Novel therapies for chronic myelogenous leukemia. Exp Hematol 2001;29:543. [88] Afar DE, Goga A, Cohen L, et al. Genetic approaches to dening signaling by the CML-associated tyrosine kinase BCRABL. Cold Spring Harbor Symp Quant Biol 1994;59:589. [89] Afar DE, McLaughlin J, Sherr CJ, Witte ON, Roussel MF. Signaling by ABL oncogenes through cyclin D1. Proc Natl Acad Sci USA 1995;92:9540. [90] Jiang Y, Zhao RC, Verfaillie CM. Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34+ cell proliferation: BCR/ABL up-regulates the cyclin-dependent kinase inhibitor, p27Kip, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity. Proc Natl Acad Sci USA 2000;97: 10538. [91] Sawyers CL. Molecular consequences of the BCRABL translocation in chronic myelogenous leukemia. Leuk Lymphoma 1993;11:101. [92] Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ. Inhibition of apoptosis by BCRABL in chronic myeloid leukemia. Blood 1994;83:2038. [93] McGahon A, Bissonnette R, Schmitt M, Cotter KM, Green DR, Cotter TG. BCRABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood 1994;83:1179.

719

[94] Cotter TG. BCRABL: an anti-apoptosis gene in chronic myelogenous leukemia. Leuk Lymphoma 1995;18:231. [95] McLaughlin J, Chianese E, Witte ON. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci USA 1987;84:6558. [96] Gishizky ML, Witte ON. Initiation of dysregulated growth of multipotent progenitor cells by bcrabl in vitro. Science 1992; 256:836. [97] Chissoe SL, Bodenteich A, Wang YF, Wang YP, Burian D, Clifton SW, et al. Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation. Genomics 1995;27:67. [98] Kurzrock R, Shtalrid M, Romero P, et al. A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukemia. Nature 1987;325:631. [99] Chan L, Karhi KK, Rayter SI, et al. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukemia. Nature 1987;325:635. [100] Quackenbush RQ, Reuther GW, Miller JP, Courtney KD, Pear WS, Pendergast AM. Analysis of the biologic properties of p230 BcrAbl reveals unique and overlapping properties with the oncogenic p185 and p210 BcrAbl tyrosine kinases. Blood 2000;95:2913. [101] McLaughlin J, Chianese E, Witte ON. Alternative forms of the BCRABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells. Mol Cell Biol 1989;9:1866. [102] Li S, Ilaria Jr RL, Million RP, Daley GQ, Van Etten RA. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med 1999;189:1399. [103] Nishimura J, Shibata K, Sadamura S, Takahira H, Hirata J, Umemura T, et al. Differences in tyrosine phosphorylated proteins between cells expressing P210bcr/abl and P190bcr/abl. Int J Hematol 1992;55:227. [104] de Jong R, van Wijk A, Haataja L, Heisterkamp N, Groffen J. BCR/ABL-induced leukemogenesis causes phosphorylation of Hef1 and its association with Crkl. J Biol Chem 1997;272:32649. [105] Okuda K, Golub TR, Gilliland DG, Grifn JD. p210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines. Oncogene 1996;13:1147. [106] Didsbury J, Weber RF, Bokoch GM, Evans T, Snyderman R. Rac, a novel ras-related family of proteins that are botulinum toxin substrates. J Biol Chem 1989;264:16378. [107] McWhirter JR, Wang JY. Effect of Bcr sequences on the cellular function of the BcrAbl oncoprotein. Oncogene 1997;15:1625. [108] Daley GQ, Ben-Neriah Y. Implicating the bcr/abl gene in the pathogenesis of Philadelphia chromosome-positive human leukemia. Adv Cancer Res 1991;57:151. [109] Chuang T-H, Xu X, Kaartinen V, Heisterkamp N, Groffen J, Bokoch G. Abr and Bcr are multifunctional regulators of the Rho GTP-binding protein family. Proc Natl Acad Sci USA 1995;92:10282. [110] Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress bers in response to growth factors. Cell 1992;70:389. [111] Estrov Z, Talpaz M, Kantarjian H, Zipf T, McClain KL, Kurzrock R. Heterogeneity in lineage derivation of Philadelphia-positive acute lymphoblastic leukemia expressing p190 BCRABL or p210 BCRABL: determination by analysis of individual colonies with the polymerase chain reaction. Cancer Res 1993;53:3289. [112] Kalousek DK, Dube ID, Eaves CJ, Eaves AC. Cytogenetic studies of hemopoietic colonies from patients with an initial diagnosis of acute lymphoblastic leukemia. Br J Hematol 1988;70:5. [113] Kantarjian HM, Talpaz M. Denition of the accelerated phase of chronic myelogenous leukemia. J Clin Oncol 1988;6:18. [114] Nanjangud G, Kadam PR, Saikia T, Bhisey AN, Kumar A, Gopal R, et al. Karyotypic ndings as an independent prognostic marker in chronic myeloid leukemia blast crisis. Leuk Res 1994;18:385.

720

A.S. Advani, A.M. Pendergast / Leukemia Research 26 (2002) 713720 European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 1996;17(Suppl 3):S7. Radich JP, Gehly G, Gooley T, Bryant E, Clift RA, Collins S, et al. Polymerase chain reaction detection of the bcrabl fusion transcript after allogeneic marrow transplantation for chronic meyloid leukemiaresults and implications in 346 patients. Blood 1995;85:2632. Lion T, Gaiger A, Henn T, Horth E, Haas OA, Geissler K, et al. Use of quantitative polymerase chain reaction to monitor residual disease in chronic myelogenous leukemia during treatment with interferon. Leukemia 1995;9:1353. Giralt SA, Kolb HJ. Donor lymphocyte infusions. Curr Opin Oncol 1996;8:96. Oda T, Tamura S, Matsuguchi T, Grifn JD, Druker BJ. The SH2 domain of ABL is not required for factor-independent growth induced by BCRABL in a murine myeloid cell line. Leukemia 1995;9:295. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 1996;56:100. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of BcrAbl positive cells. Nat Med 1996;2:561. Druker BJ, Sawyers CL, Talpaz M. Phase I trial of specic abl tyrosine kinase inhibitor, CGP 57148, in interferon refractory chronic myelogenous leukemia patients. Proc ASCO 1999;8:24a (abstract). Talpaz M, Sawyers CL, Kantarjian HM, et al. Activity of an ABL specic tyrosine kinase inhibitor in patients with BCRABL positive acute leukemia, including chronic myelogenous leukemia in blast crisis. Proc ASCO 2000;19:4a (abstract). Goldman JM, Melo JV. Targeting the BCRABL tyrosine kinase in chronic myeloid leukemia (letter). N Engl J Med 2001;344:1084. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV, Selection and characterization of BCRABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96 (3):10709. Weisberg E, Grifn JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 2000;95:3498. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance in STI-571 cancer treatment caused by BcrAbl gene mutation or amplication. Science 2001;293:876. Lim Y-M, Wong S, Lau G, Witte ON, Colicelli J. BCR/ABL inhibition by an escort/phosphatase fusion protein. Proceedings of the National Academy of Sciences of the USA. Proc Natl Acad Sci USA 2000;97:12233. Peters DG, Hoover RR, Gerlach MJ, Koh EY, Zhang H, Choe K, et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood 2001;97:1404.

[115] Asou N, Sanada I, Tanaka K, Hidaka M, Suzushima H, Matsuzaki H, et al. Inversion of chromosome 16 and bone marrow eosinophilia in a myelomonocytic transformation of chronic myeloid leukemia. Cancer Genet Cytogenet 1992;61:197. [116] Chopra R, Pu QQ, Elefanty AG. Biology of BCRABL. Blood Rev 1999;13:211. [117] Cogswell PC, Morgan R, Dunn M. Mutations in the ras protooncogenes in chronic myelogenous leukemia: a high frequency of ras mutations in bcr/abl rearrangement-negative chronic myelogenous leukemia. Blood 1989;74:2629. [118] Feinstein E, Cimino G, Gale RP. P53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci USA 1991;88: 6293. [119] Sawyers CL. The role of myc in transformation by BCRABL. Leuk Lymphoma 1993;11(Suppl 1):45. [120] Ahuja H, Bar-Eli M, Arlin Z. The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia. J Clin Invest 1991;87:2042. [121] Towatari M, Aduchi K, Kato H, Saito H. Absence of the human retinoblastoma gene product in the megakaryoblastic crisis of chronic myelogenous leukemia. Blood 1991;78:2178. [122] Cambier N, Chopra R, Strasser A, Metcalf D, Elefanty AG. BCRABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner. Oncogene 1998;16:335. [123] Collins SJ, Kubonishi I, Miyoshi I, Groudine MT. Altered transcription of the c-abl oncogene in K-562 and other chronic myelogenous leukemia cells. Science 1984;225:72. [124] Andrews DF, Collins SJ. Heterogeneity in expression of the bcrabl fusion transcript in CML blast crisis. Leukemia 1987;1:718. [125] Gaiger A, Henn T, Horth E, Geissler K, Mitterbauer G, Maier-Dobersberger T, et al. Increase of bcrabl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. Blood 1995;86:2371. [126] Beck Z, Bacsi A, Kovacs E, Kiss J, Kiss A, Balogh E, et al. Changes in oncogene expression implicated in evolution of chronic granulocytic leukemia from its chronic phase to acceleration. Leuk Lymphoma 1998;30:293. [127] Mitelman F. They cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma 1993;11:11. [128] Liu E, Hjelle B, Bishop JM. Transforming genes in chronic myelogenous leukemia. Proc Natl Acad Sci USA 1988;85:1952. [129] OBryan JP, Frye RA, Cogswell PC, et al. Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol 1991;11:501. [130] Rowley DJ, Testa JR. Chromosome abnormalities in malignant hematologic disease. Adv Cancer Res 1982;36:103. [131] Mauro MJ, Druker BJ. Chronic myelogenous leukemia. Curr Opin Oncol 2001;13:3. [132] Chronic Myeloid Leukemia Trialists Cooperative Group. Interferon-alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials. J Natl Cancer Inst 1997;89:1616. [133] Gratwohl A, Hermans J. Allogeneic bone marrow transplantation for chronic myeloid leukemia. Working Party Chronic Leukemia of the

[134]

[135]

[136] [137]

[138]

[139]

[140]

[141]

[142]

[143] [144]

[145]

[146]

[147]

[148]