Acquired loss of p53 induces blastic transformation in p210bcr/abl-expressing hematopoietic cells: a transgenic study for blast crisis of human CML

Abstract

Chronic myelogenous leukemia (CML) begins with an indolent chronic phase but inevitably progresses to a fatal blast crisis. Although the Philadelphia chromosome, which generates p210bcr/abl, is a unique chromosomal abnormality in the chronic phase, additional chromosomal abnormalities are frequently detected in the blast crisis, suggesting that superimposed genetic events are responsible for disease progression. To investigate whether loss of p53 plays a role in the evolution of CML, we crossmated p210bcr/abl-transgenic (BCR/ABLtg/−) mice with p53-heterozygous (p53+/−) mice and generated p210bcr/abl-transgenic, p53-heterozygous (BCR/ABLtg/−p53+/−) mice, in which a somatic alteration in the residual normal p53 allele directly abrogates p53 function. TheBCR/ABLtg/−p53+/− mice died in a short period compared with their wild-type (BCR/ABL−/−p53+/+), p53 heterozygous (BCR/ABL−/−p53+/−), and p210bcr/abl transgenic (BCR/ABLtg/−p53+/+) litter mates. They had rapid proliferation of blast cells, which was preceded by subclinical or clinical signs of a myeloproliferative disorder resembling human CML. The blast cells were clonal in origin and expressed p210bcr/abl with an increased kinase activity. Interestingly, the residual normal p53 allele was frequently and preferentially lost in the tumor tissues, implying that a certain mechanism facilitating the loss of p53 allele exists in p210bcr/abl-expressing hematopoietic cells. Our study presents in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210bcr/abl-expressing hematopoietic cells and provides insights into the molecular mechanism for blast crisis of human CML.