Properties of Leukemia Stem Cells in a Novel Model of CML Progression to Lymphoid Blast Crisis

Abstract : Progression of CML from chronic phase to lymphoid blast crisis is a poorly characterized event. However, at least some of the molecular events that accompany evolution of the disease have been described. One such event, mutation of the p16Ink4a/p19Arf locus, is known to occur in approximately 50% of patients developing acute lymphoid disease. Based on this observation, we generated a novel mouse model in which combination of the well-known BCR/ABL translocation with loss of function mutation at the p16Ink4a/p19Arf locus induces a very robust and authentic lymphoid blast crisis. In order to understand the earliest origins of disease pathogenesis, we have used the model to characterize leukemia stem cells (LSC) as they progress from chronic phase disease to blast crisis. Intriguingly, in the chronic phase, LSC can be derived only by introduction of BCR/ABL into normal hematopoietic stem cells (HSC). Expression of BCR/ABL at later stages of hematopoietic differentiation does not support development of disease. In contrast, upon loss of p16Ink4a/p19Arf activity, expression of BCR/ABL is sufficient to induce disease at multiple stages of hematopoietic differentiation (HSC, CLP, Pro-B, etc). These findings indicate evolution of LSC during progression to lymphoid blast crisis can occur via mutations in several different types of stem and progenitor cells, an observation that has important ramifications for the clinical management of patients with lymphoid, as compared to myeloid blast crisis. Objective/Hypothesis: We hypothesize that mutations occurring during various stages of hematopoietic development will generate a heterogeneous population of LSC in lymphoid blast crisis, and that the various classes of LSC will differ with regard to their drug sensitivity. The objective of the proposal is to characterize discrete LSC types and define methods for their eradication.