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Leukemia: Advances in Research and Treatment pp 295–325Cite as

The molecular pathogenesis of the philadelphia-positive leukemias: Implications for diagnosis and therapy

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Part of the book series: Cancer Treatment and Research ((CTAR,volume 64))

Abstract

The Philadelphia chromosome is the cytogenetic hallmark of the myeloproliferative disease chronic myelogenous leukemia (CML), and is also found in many cases of acute lymphoblastic leukemia (ALL) and some cases of acute myelogenous leukemia (AML). In 1973, Rowley demonstrated that the Philadelphia chromosome, a small form of human chromosome 22 [1], was the product of a reciprocal translocation between the long arms of chromosomes 9 and 22: t(9;22)(q34.1;qll.21) [2]. A decade later, the molecular structure of the Philadelphia chromosome was determined, showing that the Philadelphia translocation results in the juxtaposition of the human proto-oncogene c-ABL on chromosome 9 with a gene denoted BCR on chromosome 22, resulting in the generation of a chimeric BCR/ABL fusion gene [3–8]. In the ensuing years, progress has been rapid, sometimes astonishingly so. The product of the BCR/ABL gene was identified in malignant cells from CML patients as a 210-kd fusion protein, p210BCR/ABL [9]. Like other members of the abl family, the p210BCR/ABL protein was shown to be a nonreceptor protein-tyrosine kinase [10]. The role of BCR/ABL as an oncogene was strengthened with the findings that this gene could transform factor-dependent lymphoid and myeloid cells in culture to growth factor- independence and tumorigenicity [11,12], and by its ability to transform immature primary lymphoid progenitor cells in long-term in vitro culture [13]. The importance of the tyrosine kinase activity for transformation and oncogenicity was confirmed with the study of mutants that were temperature- sensitive or defective for tyrosine kinase activity [14,15]. A distinct and smaller form of Bcr/Abl protein, p190BCR/ABL, was identified in some patients with Philadelphia-positive ALL and AML, resulting from a molecular variant of the Philadelphia chromosome translocation [16-19]. Recently, animal models of the BCR/ABL leukemias have become available, employing either transgenic strains of mice carrying the BCR/ABL gene [20,21], or retroviral transduction of BCR/ABL genes into mouse bone marrow followed by bone marrow transplantation [22-24]. Thus, this group of human leukemias is now one of the best characterized at the clinical and molecular levels, and is the subject of several recent reviews [25,26].

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Van Etten, R.A. (1993). The molecular pathogenesis of the philadelphia-positive leukemias: Implications for diagnosis and therapy. In: Freireich, E.J., Kantarjian, H. (eds) Leukemia: Advances in Research and Treatment. Cancer Treatment and Research, vol 64. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3086-2_14

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