Myeloid-Biased Stem Cells as Potential Targets for Chronic Myelogeneous Leukemia

摘要

CML results from the malignant transformation of a pluripotent hematopoletic stem cell (HSC). We identified novel subsets of HSC, called Myeloid-biased (My-bi) HSC. These HSC are epigenetically programmed to generate progeny that is skewed towards the myeloid lineage. Thus, both the normal My-bi HSC and the transformed CML HSC generate a myeloidbiased progeny. Accordingly, we hypothesized that My-bi HSC are the target of transformation that can lead to CML. We are taking advantage of a mouse model for CML. We will isolate the different types of HSC that we have identified and will infect these with replication deficient retroviri containing the myeloid-associated p2lO form of the Bcr/Abl construct. If our hypothesis is correct, My-bi HSC, but not balanced or Ly-bi, HSC can be transformed to give rise to myelogenous leukemia. We have begun to generate clonally repopulated host animals and have identified linage biased HSC. We have also begun a series of experiments to define the conditions that will yield high titer retrovirus for the proposed studies. The proposed studies for the first time raise the possibility to selectively target My-bi HSC for therapy. This would leave other HSC untouched, limiting the toxicity of therapy.