Altered Microenvironmental Regulation of Leukemic and Normal Stem Cells in Chronic Myelogenous Leukemia

SummaryWe characterized leukemia stem cells (LSC) in chronic phase chronic myelogenous leukemia (CML) using a transgenic mouse model. LSC were restricted to cells with long-term hematopoietic stem cell (LTHSC) phenotype. CML LTHSC demonstrated reduced homing and retention in the bone marrow (BM), related to decreased CXCL12 expression in CML BM, resulting from increased G-CSF production by leukemia cells. Altered cytokine expression in CML BM was associated with selective impairment of normal LTHSC growth and a growth advantage to CML LTHSC. Imatinib (IM) treatment partially corrected abnormalities in cytokine levels and LTHSC growth. These results were validated using human CML samples and provide improved understanding of microenvironmental regulation of normal and leukemic LTHSC and their response to IM in CML.

Graphical AbstractFigure optionsDownload high-quality image (204 K)Download as PowerPoint slideHighlights
► CML LSC demonstrate altered proliferation, differentiation and localization
► Abnormal localization is related to leukemia-induced decrease in BM CXCL12 expression
► Altered cytokine expression confers a growth advantage to LSC over normal stem cells
► Micro-environmental changes are partially but not completely corrected by TKI treatment