BLASTIC TRANSFORMATION OF P53-DEFICIENT BONE-MARROW CELLS BY P210(BCRABL) TYROSINE KINASE/

Elastic transformation of chronic myelogenous leukemia (CML) is charac terized by the presence of nonrandom, secondary genetic abnormalities in the majority of Philadelphia(1) clones, and loss of p53 tumor suppr essor gene function is a consistent finding in 25-30% of CML blast cri sis patients, To test whether the functional loss of p53 plays a direc t role in the transition of chronic phase to blast crisis, bone marrow cells from p53(+/+) or p53(-/-) mice were infected with a retrovirus carrying either the wild-type BCR/ABL or the inactive kinase-deficient mutant, and were assessed for colony-forming ability, Infection of p5 3(-/-) marrow cells with wild-type BCR/ABL, but not with the kinase-de ficient mutant, enhanced formation of hematopoietic colonies and induc ed growth factor independence at high frequency, as compared with p53( +/+) marrow cells, These effects were suppressed when p53(-/-) marrow cells were coinfected with BCR/ABL and wild-type p53. p53-deficient BC R/ABL-infected marrow cells had a proliferative advantage, as reflecte d by an increase in the fraction of S+G(2) phase cells and a decrease in the number of apoptotic cells, Immunophenotyping and morphological analysis revealed that BCR/ABL-positive p53(-/-) cells were much less differentiated than their BCR/ABL-positive p53(+/+) counterparts. Inje ction of immunodeficient mice with BCR/ABL-positive p53(-/-) cells pro duced a transplantable, highly aggressive, poorly differentiated acute myelogenous leukemia, In marked contrast, the disease process in mice injected with BCR/ABL-positive p53(+/+) marrow cells was characterize d by cell infiltrates with a more differentiated phenotype and was sig nificantly retarded, as indicated by a much longer survival of leukemi c mice, Together, these findings directly demonstrate that loss of p53 function plays an important role in blast transformation in CML.