The BCR gene and philadelphia chromosome-positive leukemogenesis.

Recent investigations have rapidly added crucial new insights into the complex functions of the normal BCR gene and of the BCR-ABL chimera and are yielding potential therapeutic breakthroughs in the treatment of Philadelphia (Ph) chromosome-positive leukemias. The term “breakpoint cluster region (bcr)” was first applied to a 5.8-kb span of DNA on the long arm of chromosome 22 (22q11), which is disrupted in patients with CML bearing the Ph translocation [t(9; 22)(q34;q11); Refs. 1–3]. Subsequent studies demonstrated that the 5.8-kb fragment resided within a central region of a gene designated BCR (4). It is now well established that the breakpoint within BCR can be variable, and when joined with ABL, results in a hybrid Mr 210,000 (p210) or a Mr 190,000 (p 190 protein (p190; Fig. 1; Refs. 5–13). Of interest, p190 characterizes a phenotypically acute, rather than chronic, leukemia that is often, but not always, of lymphoid (rather than of myeloid) derivation (Refs. 10 and 14; Table 1). Both p210 and p190 have constitutive tyrosine kinase activity. Furthermore, the presence of the hybrid proteins perturbs the multiple functions of their normal counterparts. Understanding the biological sequelae of the molecular aberrations in Ph-positive disease has led to development of novel tyrosine kinase inhibitor therapy that is showing remarkable success in clinical trials. Herein, we review the current state of knowledge on the role of BCR alone or when joined with ABL in normal and leukemic pathophysiology and the implications of this knowledge for therapy.