The function of the pleckstrin homology domain in BCR–ABL-mediated leukemogenesis

Abstract

The BCR–ABL tyrosine kinase is central to the pathogenesis of chronic myeloid leukemia (CML) and Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Depending on the breakpoint in BCR, several BCR–ABL variants can be generated (Figure 1a), such as p190BCR–ABL and p210BCR–ABL, which are detected in the majority of cases of Ph-positive ALL and CML, respectively.1 The p190BCR–ABL isoform was previously reported to show elevated tyrosine kinase activity,2, 3 although the structural basis for increased kinase activity has not been established and kinase activity alone fails to explain the predilection of p190BCR–ABL for transformation of lymphoid cells. At the sequence level, the genetic information retained in p210BCR–ABL but not in p190BCR–ABL encodes the diffuse poorly differentiated B-cell lymphoma (DBL)-like and pleckstrin homology (PH) domains of BCR. Although earlier studies have suggested a positive role for the DBL-like domain in p210BCR−ABL-induced transformation,4 the function of the PH domain in leukemogenesis has not been studied in isolation. In this study, we used a rare, naturally occurring variant of BCR–ABL (p200BCR–ABL; Figure 1a) that retains the DBL-like, but not the PH domain to analyze the role of the PH domain in BCR–ABL-induced leukemia.