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Despite the efficacy of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), malignant long-term hematopoietic stem cells (LT-HSC) persist as a source of relapse. However, LT-HSC are heterogenous and the most primitive, drug-resistant LT-HSC subpopulations are not well characterized.In normal hematopoiesis, self-renewal and long-term reconstitution capacity is enriched within LT-HSCs with low c-Kit expression (c-KIT Low ). Here, using a transgenic CML mouse model, we found that long-term engraftment and leukemogenic capacity were restricted to c-KIT Low CML LT-HSC. CML LT-HSC demonstrated enhanced differentiation with expansion of mature progeny following exposure to the c-KIT ligand, stem cell factor (SCF). Conversely, SCF deletion led to depletion of normal LT-HSC but increase in c-KIT Low and total CML LT-HSC with reduced generation of mature myeloid cells. CML c-KIT Low LT-HSC showed reduced cell cycling, and expressed enhanced quiescence and inflammatory gene signatures. SCF administration led to enhanced depletion of CML primitive progenitors but not LT-HSC after TKI treatment. Human CML LT-HSC with low or absent c-KIT expression were markedly enriched after TKI treatment. We conclude that CML LT-HSC expressing low c-KIT levels are enriched for primitive, quiescent, drug-resistant leukemia initiating cells and represent a critical target for eliminating disease persistence.

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