Malignant-like transformation of normal stem and progenitor cells by myeloid leukemia

It has long been known that leukemic cells disrupt normal patterns of blood cell formation, but little is understood about mechanisms. It has generally been assumed that normal hematopoietic stem and progenitor cells (HSPC) are simply out-competed for space by malignant cells. We designed a strategy to determine if leukemic cells alter intrinsic properties and functions of normal HSPCs. Chimeric mice were generated by transplantation of normal marrow and marrow from an inducible transgenic model of chronic myelogenous leukemia (CML). With induction of CML, the composition of the marrow changed dramatically, and normal HSPCs divided more readily and lost their ability to produce lymphocytes. In contrast, only modest changes were recorded in numbers of normal hematopoietic stem cells (HSCs). However, these stem cells were not unscathed, and had reduced reconstitution and self-renewal potential upon transplantation. Interestingly, the normal bystander cells acquired gene expression patterns resembling their neighboring malignant counterparts. This suggested that much of the leukemia signature is mediated by extrinsic factors in the environment. Leukemic mice were generated by transplanting equal numbers of CD45.2+ BCR-ABL x SCL-tTA transgenic murine bone marrow along with CD45.1+ bone marrow into CD45.1+ hosts. After induction of the leukemic cells by removal of Tet water, 4 weeks later the CD45.1+ LT-HSC (CD150+ CD48- KSL) were sorted from controls or leukemic mice intro Trizol. Samples were prepared for microarray analysis after RNA isolation using the Nugen kit (Ovation Pico WTA System V2).