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BCR/ABL Genes and Leukemic Phenotype: from Molecular Mechanisms to Clinical Correlations

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BCR/ABL Genes and Leukemic Phenotype: from Molecular Mechanisms to Clinical Correlations Oncogene (2002) 21, 8652 – 8667 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc BCR/ABL genes and leukemic phenotype: from molecular mechanisms to clinical correlations Fabrizio Pane*,1, Mariano Intrieri1,2, Concetta Quintarelli1, Barbara Izzo1, Giada Casadei Muccioli1 and Francesco Salvatore1 1CEINGE Biotechnologie Avanzate, and Dipartimento di Biochimica e Biotecnologie Mediche, Facolta` di Medicina, Universita` di Napoli Federico II, Italy; 2Dipartimento STAT, Facolta` di Scienze MFN, Universita` degli Studi del Molise - Isernia, Italy The Philadelphia chromosome (Ph), a minute chromo- leukemias, the intimate role of the BCR/ABL protein some that derives from the balanced translocation in leukemic transformation has not yet been between chromosomes 9 and 22, was first described in completely elucidated. The knowledge of the role of 1960 and was for a long time the only genetic lesion BCR/ABL fusion gene in leukemia is further consistently associated with human cancer. This chro- complicated by cytogenetic and epidemiological mosomal translocation results in the fusion between the observations. This hybrid gene was originally 5’ part of BCR gene, normally located on chromosome described in a chronic type of leukemia affecting 22, and the 3’ part of the ABL gene on chromosome 9 the myeloid compartment, the chronic myelogenous giving origin to a BCR/ABL fusion gene which is leukemia (CML), and is present in almost all the transcribed and then translated into a hybrid protein. CML cases with a classical clinical picture, which is Three main variants of the BCR/ABL gene have been now considered the hallmark (Bennett et al., 1994). described, that, depending on the length of the sequence However, unlike other genetic lesions that are of the BCR gene included, encode for the p190BCR/ABL, specifically associated with particular types of leuke- P210BCR/ABL, and P230BCR/ABL proteins. These three mias (Rowley, 1998), the BCR/ABL hybrid gene is main variants are associated with distinct clinical types not restricted to CML, but it can also be found in a of human leukemias. Herein we review the data on the significant proportion of acute lymphoblastic leuke- correlations between the type of BCR/ABL gene and the mia (ALL) and less frequently in other chronic and corresponding leukemic clinical features. Lastly, drawing acute hemopoietic tumors (Melo, 1996). We described on experimental data, we provide insight into the a relatively benign and rather rare form of different transforming power of the three hybrid BCR/ myeloproliferative disease that we called ‘Neutrophi- ABL proteins. lic-chronic myeloid leukemia’ (CML-N), which is also Oncogene (2002) 21, 8652 – 8667. doi:10.1038/sj.onc. associated with a BCR/ABL gene, that shows a novel 1206094 position for the breakpoint in the BCR gene far downstream from the breakpoints already described Keywords: Philadelphia chromosome; Ph positive leu- (Pane et al., 1996b). Therefore, the identification of kemias; molecular pathogenesis; phenotype of leukemia this subset of patients carrying the novel type of BCR/ABL gene led to the hypothesis that the structure of this gene and, in particular, the location Introduction of the breakpoint on the BCR sequences correlates with the leukemic phenotype (Pane et al., 1996b). A Ph-positive leukemias have been the object of masterly account of these data and their far reaching extensive studies to define at molecular and cellular implications can be found in Melo (1996). level the complex mechanisms whereby the hybrid To minimize overlapping with the excellent reviews BCR/ABL protein may disrupt, in hemopoietic devoted to the intracellular interactions of BCR/ABL precursors, the maturation and replication processes proteins that have appeared in recent years (Faderl et and the physiological response to cytokines and al., 1999; Holyoake, 2001) or that are included in this growth factor leading, ultimately, to their neoplastic issue of the journal, we first trace the milestones that transformation. Although the expression of the have culminated in today’s state of the art, and then hybrid BCR/ABL protein is presumed to be an early discuss: (i) the molecular structure of BCR/ABL fusion pathogenic event and its elevated tyrosine kinase genes; (ii) the correlation between leukemic clinical activity to be a central event in Ph positive features and the position of the breakpoint in the BCR gene; (iii) the clinical characteristics of the CML-N cases described so far; and (iv) the hypothesis that *Correspondence: F Pane, CEINGE and Dipartimento di Biochimica could explain at molecular level the differential e Biotecnologie Mediche, Universita` di Napoli Federico II, Via S. transforming power of the various BCR/ABL fusion Pansini 5, 80131 Naples, Italy; E-mail: [email protected] proteins. BCR/ABL genes and leukemic phenotype F Pane et al 8653 Milestones neoplasias. The identification of an abnormally large (8.0 kb) v-ABL related mRNA in Ph positive cell lines The history of the hybrid BCR/ABL gene started in and in CML cells, but not in normal cells and in Ph 1960, when an abnormal, shortened chromosome 22, negative leukemias (Gale and Canaani, 1984), and the termed the Philadelphia chromosome, was described in characterization of a large (210 kDa) ABL related the leukemic cells of a patient affected by chronic phosphoprotein, the P210 (Konopka et al., 1984), myeloid leukemia (Nowell and Hungerford, 1960). reinforced the concept that CML was related to a Only 13 years later, the use of quinacrine fluorescence fusion gene. Importantly, the tyrosine kinase activity of and Giemsa banding in chromosome studying, allowed P210 resembled that of protein v-ABL (Witte et al., to clarify that Ph chromosome is the result of a 1980; Davis et al., 1985), which was phosphorylated, translocation of part of chromosome 22 to chromo- whereas the 145 kDa c-ABL protein which was not some 9 (Rowley, 1973). The molecular characterization phosphorylated in vivo, in normal cells (Konopka and of this translocation was facilitated when the c-ABL Witte, 1985). gene, the human homologous of v-ABL, an oncogene The definitive proof of the presence of a fusion gene originally identified in the Abelson murine leukemia in CML cells, came from the studies of Shtivelman et virus, was localized to the long arm of the chromosome al. (1995) that first cloned the full length cDNA 9 (Heisterkamp et al., 1982). Two ABL probes, which corresponding to the 6.0 kb cABL encoding transcript, normally map to chromosome 9, were shown to and used the 5’ part of this cDNA to clone the CML- hybridize on chromosome 22q- (the Ph chromosome) specific transcript from cDNA libraries prepared from of somatic cell hybrids originating from human CML both K562 and EM2 PH positive cell lines. The leukocytes and rodent cells (de Klein et al., 1982), sequence analysis of these transcripts isolated from while sequences of the c-sis oncogene, generally found both cell lines revealed that they contain a novel 5’ on chromosome 22, were shown to be translocated to sequence fused in frame with c-ABl exon 2, and the chromosome 9 in CML cells (Groffen et al., 1983). interestingly, a genomic fragment which hybridized to These studies indicated a reciprocal translocation for these non-ABL sequences contained the M-bcr region the Ph chromosome, and suggested that activation of previously identified by Groffen et al. (1984). Taken the transforming potential of the c-ABL proto- together, these data suggested that the 8 kb CML- oncogene was an important consequence of the specific mRNA contains the BCR joined to the c-ABL translocation. The cloning of the BCR/ABL break- sequences that was transcribed from a BCR/ABL point was the subsequent milestone. Heisterkamp and fusion gene. In addition the authors suggested that colleagues applied the ‘chromosome walking’ technique the amino terminal substitution was responsible for the to show a chromosomal breakpoint within a 14 kb increased tyrosine kinase activity of the ABL-derived sequence of chromosome 9 homologous to the v-ABL, sequences. These first but extremely important data in one of three patients with CML (Heisterkamp et al., open the way to a huge amount of studies on the 1983). However, the chromosome 9 rearrangement was structure of this hybrid gene and on molecular not evident in the remaining two patients, and this mechanisms of Ph positive leukemias. prompted Groffen et al. (1984) to direct their attention to chromosome 22 breakpoints. They used the sequences complementary to chromosome 22 Molecular structure of BCR/ABL genes previously isolated from the genomic clone of the positive CML patients as probe to screen for genomic At molecular level, the Ph translocation results in the rearrangements, and found a rearrangement of chro- juxtaposing of the 5’ part of the BCR gene to the 3’ mosome 22 in a second CML patient. Noteworthy, this part of the ABL gene, and, depending on chromosomal second rearrangement of chromosome 22 mapped very breakpoint locations, different parts of these two genes closely (1 kb) to that identified in the first positive may be included in the oncogenic fusion gene (Table CML patient. When the same probe and restriction 1). analysis was applied to a series of 17 leukemic patients, The ABL gene is a gene encoding a non receptor all but two cases (both Ph chromosome negative) tyrosine kinase, which spans a 230 kb region at band showed a chromosome 22 rearrangement clustered q34 of chromosome 9 and consists of 11 exons, with within a 5.8
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