Therapy resistant primitive stem cells in chronic myelogenous leukemia are characterized by low c-Kit expression and altered SCF response

Leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) resist elimination with tyrosine kinase inhibitors (TKI) and persist as a source of disease recurrence. LSC populations are heterogeneous, but the most primitive, drug-resistant subsets are not well characterized. Previous studies indicate that variable cell-surface expression of the c-Kit receptor identifies heterogeneous hematopoietic stem cells (HSC) populations. We found that c-Kit expression is reduced on CML LSC compared to normal HSC. Long-term engraftment and leukemia generation capacity was restricted to low c-Kit expressing (c-KitLow) LSC, which showed increased quiescence and inflammatory gene signatures expression. The c-Kit ligand, stem cell factor (SCF), expanded normal HSC but drove maturation of CML LSC. The proportion of c-Kitlow LT-HSC was increased with TKI treatment. Supplementary SCF treatment enhanced elimination of committed but not primitive CML LT-HSC in TKI-treated mice. Low c-Kit expression identifies primitive, treatment-resistant LSC subpopulations with distinct regulatory characteristics, that are critical therapeutic targets. Overall design: Comparing CML c-KitHigh and c-KitLow Leukemic stem cells against Normal c-KitHigh and c-KitLow Hematopeitic stem cell in murine bone marrow