Bcr/Abl, leukemogenesis, and genomic instability: a complex partnership

Abstract

For many years, the issue of genomic instability in chronic myelogenous leukemia (CML) has been one of “guilt by association”. Even before much of the molecular pathophysiology of CML was known, investigators had noted that patients with advanced CML acquired additional cytogenetic abnormalities. Interestingly, there is a relatively short list of common secondary chromosomal cytogenetic changes, including an additional copy of the Philadelphia chromosome, trisomy 8, trisomy 19, isochromosome 17q, and loss of the Y chromosome [1]. Transgenic mice expressing the P190 form of BCR/ABL have also been shown to develop karyotypic abnormalities during the later stages of their leukemic illness, most commonly trisomy involving chromosomes 12, 14, or 17, alone or in combination [2]. Prolonged expression of the P210 form of BCR/ABL in the murine myeloid cell line 32D has been demonstrated to be associated with the development of aneuploidy and complex chromosomal translocations [3]. These and other findings have led investigators to postulate that Bcr/Abl expression itself might be responsible to such secondary genetic changes. Proving such a connection, however, is a complex challenge. Solid tumors often demonstrate a variety of cytogenetic abnormalities [4], most of which are likely the consequence, rather than the cause, of malignant transformation. Therefore, it is conceivable that the additional cytogenetic abnormalities seen in CML could merely reflect stochastic changes due to a prolonged leukemia process. Alternatively, given the impact of Bcr/Abl on factors regulating cell survival, apoptosis, and DNA repair, the hypothesis that Bcr/Abl itself could lead to genomic instability independent of its leukemogenic effect is of considerable interest. One recent approach to this question has been to mate P190BCR/ABL transgenic mice [5] with the transgenic strain