Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML

Chronic myelogenous leukemia (CML) begins with an indolent chronic phase bu t inevitably progresses to a fatal blast crisis. Although the Philadelphia chromosome, which generates p210(bcr/abl) is a unique chromosomal abnormali ty in the chronic phase, additional chromosomal abnormalities are frequentl y detected in the blast crisis, suggesting that superimposed genetic events are responsible for disease progression. To investigate whether loss of p5 3 plays a role in the evolution of CML, we crossmated p210(bcr/abl)-transge nic (BCR/ABL(tg/-)) mice with p53-heterozygous (p53(+/-)) mice and generate d p210(bcr/abl)-transgenic, p53-heterozygous (BCR/ABL(tg)/-p53(+/-)) mice, in which a somatic alteration in the residual normal p53 allele directly ab rogates p53 function. The BCR/ABL(tg/-)p53(+/-) mice died in a short period compared with their wild-type (BCWABL(-/-)p53(+/+)), p53 heterozygous (BCR /ABL(-/-)p53(+/-)), and p210(bcr/abl) transgenic (BCR/ABL(tg/-)p53(+/+)) li tter mates. They had rapid proliferation of blast cells, which was preceded by subclinical or clinical signs of a myeloproliferative disorder resembli ng human CML, The blast cells were clonal in origin and expressed p210(bcr/ abl) with an increased kinase activity. Interestingly, the residual normal p53 allele was frequently and preferentially lost in the tumor tissues, imp lying that a certain mechanism facilitating the loss of p53 allele exists i n p210(bcr/abl)-expressing hematopoietic cells. Our study presents in vivo evidence that acquired loss of p53 contributes to the blastic transformatio n of p21(bcr/abl)-expresslng hematopoietic cells and provides insights into the molecular mechanism for blast crisis of human CML.