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Role of p53 in leukemogenesis of chronic myeloid leukemia

This review attempts to provide current information on the role played by the p53 gene in normal and leukemic hematopoiesis with particular emphasis on chronic myeloid leukemia. On the basis of the currently available data we can argue that p53 acts as a negative regulator of proliferation of myeloid mature cells and CD34+ progenitors, and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. The p53‐dependent pathway is also regulated by several proteins, including p16, p21, p27 (cyclin‐dependent kinase [CDK] inhibitors), and a few oncogenes (bcl‐2, bax, MDM‐2). Although there is some information about the changes in the p53 gene seen in various types of leukemia, the functions and biological importance of these changes in the pathogenesis of leukemia are still largely elusive. During the past several years, accumulated evidence suggests that changes in the p53 gene are commonly associated with blast crisis of chronic myeloid leukemia (CML) but rarely with chronic phase, and they are represented by rearrangements, deletions and point mutations. As for most of the tumors, the majority of point mutations occur between exons 4 and 8 (hot regions). In patients with CML in blastic crisis the most frequent mechanism of p53 inactivation is complete deletion of one allele in association with a point mutation in the remaining allele. As far as the loss of p53 function in CML patients in blastic crisis is concerned, we believe that it can play a key role, in combination with other genetic changes (p210 BCR/ABL, Rb gene abnormalities, CDK inhibitors alterations), in inducing disturbances in proliferation, differentiation and apoptosis of the leukemic clone. However, the exact relationship between p210 BCR/ABL, the mutant p53, and putative alterations in CDK inhibitors (p21, p16, etc.) in the pathogenesis of blastic transformation of CML needs to be clarified. We think that experiments designed to ascertain whether sustained expression of a mutant p53 is capable of causing differentiation arrest of Ph‐positive hematopoietic cells in vitro may shed more light on this issue. It is also conceivable that a therapeutically‐induced correction of the expression of CDK inhibitors in p53 mutant CML cells can significantly influence the cell cycle machinery and possibly suppress the increased proliferative activity of blastic cells. Hopefully, highly efficient and targeted wild‐type p53 delivery vectors may, in the future, lead to a substantial clinical improvement in CML patients carrying p53 abnormalities and undergoing a blastic transformation of the disease.