Expression & function of p21Cip1 in chronic leukemia

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Chronic myeloid leukemia originates from hematopoietic stem cells harboring the fusion protein, p210bcr/abl. As a constitutively active tyrosine kinase, BCR/ABL disrupts numerous cellular events including cell proliferation and survival. In the current proposal, experimental designs will address the possible role of a cyclin-dependent kinase inhibitor, p21Cip1 in contributing to the aberrant cell cycle and survival of BCR/ABL-hematopoietic cells. Previous findings identified positive and negative role of p21 in cell proliferation. In addition, p21 can function as an anti-apoptotic protein and has been shown to render transformed cells resistant to anti-cancer drugs. Of particular interest to CML, p21 protein is detected at higher levels in BCR/ABL-positive cells, compared to normal cells. Although highly labile, p21 protein is stabilized by phosphorylation mediated by AKT, an anti-apoptotic protein activated in CML. Based on these studies, it is intriguing to test whether p21Cip1 might contribute to the enhanced cell proliferation and survival observed in CML. RNA and protein studies will investigate the mechanism by which p21Cip1 is regulated in normal and BCR/ABL hematopoietic cells. Treatment with STI571 will delineate the contributing role of BCR/ABL tyrosine kinase activity in p21 regulation. Retroviral introduction of BCR/ABL into hematopoietic progenitors from p21-wildtype, -hemizygous, and -null mice will determine the contributing role of p21 in BCR/ABL-transformation. Syngeneic transplantations of these cells will assess the impact of the varying p21 levels on the onset and progression of CML in vivo.