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Modeling Philadelphia Chromosome Positive Leukemias

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Modeling Philadelphia Chromosome Positive Leukemias Oncogene (2001) 20, 5644 ± 5659 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Modeling Philadelphia chromosome positive leukemias Stephane Wong3 and Owen N Witte*1,2,3 1Howard Hughes Medical Institute, University of California, Los Angeles, California, CA 90095-1662, USA; 2Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, CA 90095-1662, USA; 3Molecular Biology Institute, University of California, Los Angeles, California, CA 90095-1662, USA The Ph chromosome has been genetically linked to CML common. In the blast crisis phase, blood and marrow and ALL. Its chimeric fusion gene product, BCR ± ABL, mature cells are displaced by immature blasts. More can generate leukemia in mice. This review will discuss than 50% of patients enter a myeloid blast stage selected model systems developed to study BCR ± ABL resembling acute myeloblastic leukemia (AML). A pre- induced leukemia and focuses on what we have learned B blast stage similar to acute lymphoid leukemia (B- about the human disease from these models. Five main ALL) accounts for 30% of patients, and erythroid experimental approaches will be discussed including: (i) blasts develop in 10% of patients. Rarely do T cell Reconstitution of mice with bone marrow cells retro- blasts (T-ALL) evolve (Colleoni et al., 1996; Fabbiano virally transduced with BCR ± ABL; (ii) Transgenic mice et al., 1998). During progression to blast phase, over expressing BCR ± ABL; (iii) Knock-in mice with BCR ± 80% of patients develop additional chromosome ABL expression driven from the endogenous bcr locus; abnormalities (reviewed in Mitelman, 1993). This (iv) Development of CML-like disease in mice with loss suggests that genetic aberrations in addition to the of function mutations in heterologous genes; and (v) ES Ph chromosome are necessary for chronic phase CML in vitro hematopoietic dierentiation coupled with to develop to blast crisis. regulated BCR ± ABL expression. Oncogene (2001) 20, The Ph chromosome results from a reciprocal 5644 ± 5659. translocation, between chromosomes 9 and 22 t(9;22)- (q34;q11) (Nowell and Hungerford, 1960; Rowley, Keywords: BCR ± ABL; mouse model; leukemia 1973). The telomeric segment of chromosome 9q34 encoding the ABL tyrosine kinase gene is fused to the centromeric segment of chromosome 22q11 encoding the BCR gene (see Figure 1). This forms a chimeric BCR ± ABL mRNA and protein product. The alter- Introduction native reciprocal translocation product, ABL ± BCR, is thought not to play a role in leukemogenesis and will The Philadelphia chromosome was the ®rst consistent not be discussed further (Lazaridou et al., 1994; Melo chromosomal abnormality linked to a speci®c human et al., 1993, 1996). Depending on the breakpoint cancer, chronic myeloid leukemia (CML) (Nowell and positions within the BCR and ABL genes, dierent Hungerford, 1960). CML accounts for 15 ± 20% of forms of BCR ± ABL are generated. Most breakpoints human leukemia (Ghaari et al., 1999). CML is a within ABL occur between exons 1a and 1b to generate clonal disorder originating in the hematopoietic stem BCR ± ABL mRNA with BCR sequences fused to ABL cell (HSC) (Delforge et al., 1999; Fialkow et al., 1967, exon a2. Breakpoints within the BCR locus occur over 1977; Holyoake et al., 1999; and reviewed in Kabar- a large area spanning over 20 exons. Three breakpoint owski and Witte, 2000; Raskind and Fialkow, 1987; cluster regions (bcr) within BCR are most frequently Takahashi et al., 1998; Yoe et al., 1987). It can be involved. The major breakpoint cluster region (M-bcr) regarded as a biphasic disease (reviewed in Clarkson et generates an mRNA product with either a b2a2 or al., 1997). The ®rst stage, chronic phase (cpCML), is b3a2 junction due to alternative splicing which encodes characteristically indolent with clinical features includ- a 210 Kd chimeric protein p210BCR ± ABL (Ben-Neriah et ing a large increase in the number of myeloid al., 1986; Heisterkamp et al., 1985; Konopka et al., precursors and their progeny. Numbers of mature 1984; Shtivelman et al., 1985). A minor breakpoint neutrophils as well as basophils and eosinophils are cluster region (m-bcr) junction in BCR produces a elevated in the blood. In the bone marrow there is also smaller 185/190 Kd chimeric protein (Chan et al., 1987; an increase in the ratio of myeloid to erythroid cells. Clark et al., 1987; Fainstein et al., 1987; Walker et al., Splenomegaly, hepatomegaly and mild anemia are 1987). Recently, a larger 230-kd chimeric protein P230BCR ± ABL has been identi®ed generated from a g- bcr breakpoint (Saglio et al., 1990). Other fusion events leading to expression of *Correspondence: ON Witte, HHMI/UCLA, 675 Charles E Young Drive South, Room 5-748 MRL Bldg, Los Angeles, CA 90095-1662, activated forms of ABL occur in leukemia. Rare cases USA; E-mail: [email protected] of human ALL express a TEL ± ABL fusion (Golub et Models of Ph+ leukemias S Wong and ON Witte 5645 Figure 1 Locations of the breakpoints in the BCR and ABL genes and structure of the chimeric proteins derived. Three main breakpoint regions within the BCR genome are responsible for generating the three predominant forms of BCR ± ABL protein. The minor breakpoint cluster (m-BCR) spans 54-kb and results in an e1a2 7.0 kb mRNA that generates P185. The major breakpoint cluster (M-BCR) spans 5.8 kb and results in either a b2a2 or b3a2 8.5 kb mRNA producing P210. A third breakpoint cluster located at the 3' end of the gene (g-BCR) generates an e19a2 9.0 kb mRNA forming P230. Regardless of the exact breakpoint in ABL, BCR sequences are most often fused to ABL exon a2 in the hybrid transcript. BCR domains include: OLIGO=oligomerization domain; A and B=SH2 domain binding regions; S/TKINASE=serine/threonine kinase domain; DBL/ CDC24=Dbl homology domain; PH=Pleckstrin homology domain; RACGAP=Rac-GTPase domain. ABL domains include: MYR=myristoylation site; SH3 and SH2 domains; SH1KINASE=tyrosine kinase domain; NLS=nuclear localization domains; DNA=DNA binding site; ACTIN=F and G actin binding sites al., 1996; Papadopoulos et al., 1995). In mice, the its ecacy, with 98 ± 100% complete hematologic original viral form of ABL (GAG ± ABL) is a chimeric remission (Druker et al., 2001). protein in which sequences encoding the ®rst exon and In addition to the tyrosine kinase domain, BCR ± part of the second exon (a2) of ABL are replaced by ABL contains oligomerization (McWhirter et al., those encoding the viral GAG protein. GAG ± ABL is 1993; Muller et al., 1991) SH2 (Afar et al., 1994; associated with B-ALL as well as other leukemias Goga et al., 1995), autophosphorylation (Pendergast (reviewed in Rosenberg and Witte, 1988). et al., 1993a), actin binding (McWhirter and Wang, Oncogenic forms of ABL have highly elevated levels 1991, 1993; Van Etten et al., 1994), and DNA of tyrosine kinase activity compared to c-ABL. The binding (Kipreos and Wang, 1992) motifs important tyrosine kinase activities of GAG ± ABL, P185BCR ± ABL for transformation (see Figure 1). The oligomeriza- and P210BCR ± ABL correlate with their transformation tion domain of BCR ± ABL is essential for transfor- potencies in several systems (Lugo et al., 1990). mation (Maru et al., 1996a; McWhirter et al., 1993). Tyrosine kinase inactive mutants of BCR ± ABL and Other domains such as the Grb2 binding site are GAG ± ABL lose their transforming potential (Engel- required for transformation of ®broblasts to ancho- man and Rosenberg, 1987; Pendergast et al., 1993a; rage independence (Pendergast et al., 1993b) but not Ponticelli et al., 1982; Witte et al., 1980, 1981). These of hematopoietic cell lines to growth factor indepen- ®ndings have supported the essential role of deregu- dence (Cortez et al., 1995). In vivo leukemogenesis lated tyrosine kinase activity in transformation by ABL studies are important to determine the signi®cance of oncogenes, a factor exploited by the ABL kinase these BCR ± ABL domains. inhibitor STI571, a 2-phenylaminopyrimidine that There is strong association of the three main forms speci®cally inhibits the tyrosine kinase activity of of BCR ± ABL with speci®c types of human leukemias. ABL, PDGF, and C-KIT (Buchdunger et al., 1995). P210BCR ± ABL is generally considered as the pathogno- Phase 1 clinical trial studies of Ph+ chronic phase monic marker of CML and is also associated with CML patients treated with STI571 have demonstrated approximately one third of adult Ph+ ALLs (Deininger Oncogene Models of Ph+ leukemias S Wong and ON Witte 5646 et al., 2000) and on occasion, acute myeloid leukemia had a 16% incidence of macrophage tumors, and a (AML) (Kantarjian et al., 1991) and myeloma (Martiat much higher incidence of erythroid leukemia. Neither et al., 1990). P185BCR ± ABL is linked to the remaining strain developed a CML-like disease (see Table 1). two-thirds of Ph+ ALL cases not associated with In 1990, several groups demonstrated that P210 can P210BCR ± ABL (Kantarjian et al., 1991; Melo, 1996; induce a CML-like disease in mice (Daley et al., 1990; Secker-Walker et al., 1988). In addition, P185BCR ± ABL Kelliher et al., 1990). The experimental strategy was to is linked to 3% of atypical CML cases with enrich for HSC expression of P210. Mice were treated monocytosis (Melo et al., 1994), and in some AML with 5-FU to kill cycling cells and enrich for HSC cases (Kurzrock et al., 1987) and lymphoma (Mitani et populations. Quiescent HSCs are induced to cycle with al., 1990). The recently identi®ed P230BCR ± ABL is mainly cytokine mixtures prior to infection with retroviral associated with neutropenic CML (Pane et al., 1996) as vectors expressing P210. Reconstitution of lethally well as some cases of CML (Wilson et al., 1997).
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