Selective expression and constitutive phosphorylation of Src-homology-2 and collagen-homology domains proteins in the CD34(+) fraction of chronic myelogenous leukemias

The BCR/ABL fusion protein is a constitutively active tyrosine kinase that is responsible for the pathogenesis of chronic myelogenous leukemia (CML), Clinically, CML is characterized by a chronic phase (CP) that eventually terminates into a blast crisis (BC), BC transformation is associated with accumulation of CD34(+) blasts. We investigated the expression and phosphorylation of Src-homology-2 and collagen-homology domains (Shc) proteins in subpopulations of CML primary cells. Shc polypeptides are tyrosine kinase substrates that are constitutively tyrosine-phosphorylated in continuous cell lines of CML origin. High levels of Shc expression were found in the CD34(+) cells from CML-BC, CML-CP and normal bone marrow, In contrast, CD34(-) fractions from CML-CP and normal bone marrow expressed low levels of p46(Shc). Shc proteins were constitutively phosphorylated in the CD34(+) fractions from CML cells (both CP and BC), but not in normal CD34(+) cells. These data bear implications for the role of Shc in normal hemopoiesis and CML leukemogenesis: (a) dramatic changes of Shc expression during terminal differentiation of hemopoietic cells adds a further level of regulation to the signal transduction function of Shc; and (b) constitutive Shc tyrosine-phosphorylation in the rare CD34(+) cells of CML-CP might contribute to the selection of this subpopulation during the blast crisis transformation of CMLs.