Leukemia stem cells in a genetically defined murine model of blast-crisis CML

Insights into the stem cells of chronic myeloid leukemia

“…[35][36][37] More stringent dissection of the cell types able to regenerate a CML-like disease using transplants of highly purified transduced targets showed that neither purified common myeloid progenitors nor granulomonocytic progenitors were competent in contrast to upstream populations more enriched in HSCs. 38,39 These observations provide additional evidence supporting the HSC origin of CML in patients. They also argue against the theoretical possibility that BCR-ABL could be sufficient to initiate a self renewal program in downstream progenitors, in contrast to other types of genetic events that use this mechanism to initiate blast crisis …”

“…[39][40][41] The variable, but generally long, phase that precedes the diagnosis of chronic phase CML also suggests a high variability in the precise stage of the disease when the diagnosis will be made. This variability is unquestionably further enhanced by the fact that more and more CML patients are being diagnosed by chance (before they have become symptomatic) as part of a routine check-up that reveals an elevated white blood cell count.…”

“…40 It is interesting that these findings add to the accumulating experimental evidence that certain mutations are sufficient to reactivate or confer self-renewal activity upon cells in which such programs had previously been thought to be normally extinguished. 38,39,41,[46][47][48] The anatomy of primitive elements in chronic phase CML clones…”

Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo

“…7 However, mechanistic studies on downstream signals responsible for the BCR/ABL-mediated transformation phenotype are hindered by the lack of studies in HSC-initiated in vivo models. 8 Rac GTPases play integral roles in HSC and progenitor (HSC/P) proliferation, survival, homing, and engraftment. 9,10 Using a retroviral transduction model, we showed that the deficiency of the hematopoietic-specific Rac2 GTPase, but not Rac1 alone, prolonged survival of mice with myeloproliferative disease (MPD).…”

BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress

“…This effect is in concordance with the report that normal murine hematopoietic stem cells are very sensitive to irradiation in comparison with BCR/ABL-positive counterparts. 22 The experimental conditions applied here reflected two clinical situations where chromosomal instability is acquired spontaneously during the disease course (ROS-induced) and after high-dose chemo/radiotherapy treatment before hematopoietic transplantation (irradiation-induced) to address the dilemma whether the accumulation of additional chromosomal aberrations in CML is driven by BCR/ABL and/or by already preexisting mechanism(s) responsible for t (9;22). Our work demonstrated that the presence of BCR/ABL significantly enhanced chromosomal instability (aneuploidy, translocations, truncations) induced by ROS and g-irradiation; however, we cannot exclude the possibility that preexisting conditions, which generate t(9;22), may work in concert with BCR/ABL to destabilize chromosomes.…”