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.

Role of Dok-1 and Dok-2 in Leukemia Suppression

“…To test this hypothesis genetically in vivo, we made use of a Tec-p210 bcr/abl transgenic model. Tec-p210 bcr/abl TM are faithful animal models of CML as they develop a chronic leukemic phase after a long latency, followed by an acute terminal phase that is reminiscent of a CML blastic crisis with appearance of blasts in the PB and organ infiltration (15,16). Therefore, we crossed Tec- p210 bcr/abl TM with Dok-1 Ϫ/Ϫ and Dok-2 Ϫ/Ϫ mutants and assessed whether their inactivation would impact on the biology of the disease.…”

Role of Dok-1 and Dok-2 in Myeloid Homeostasis and Suppression of Leukemia

“…However, it is of note that in case of patients with CML, blast crisis mostly results in myeloid or B cell leukemia/lymphoma, usually not in the T cell variety. That Bcr-Abl mice carrying a p53 mutation also developed T cell lymphoma suggests involvement of genetic background (21).…”

Consequences of BCR‐ABL Expression within the Hematopoietic Stem Cell in Chronic Myeloid Leukemia

“…Recently improved methods for retroviral transduction of bone marrow populations enriched for stem cells [102] and the development of transgenic mice in which BCR-ABL expression is under the control of lineage-specific promoters [98] have provided more reproducible models of cpCML-like myeloproliferative disease. The current availability and future development of many gene-targeted mouse strains validate a genetic approach to evaluate mechanisms by which BCR-ABL deregulates normal hematopoietic control [103][104][105].…”