The IL-2/CD25 axis maintains distinct subsets of chronic myeloid leukemia-initiating cells

Just as normal stem cells require niche cells for survival, leukemia-initiating cells (LICs) may also require niche cells for their maintenance. Chronic myeloid leukemia (CML) is caused by the activity of BCR-ABL, a constitutively active tyrosine kinase. CML therapy with tyrosine kinase inhibitors is highly effective; however, due to the persistence of residual LICs, it is not curative. Several factors are known to support CML LICs, but purification of LICs and a thorough understanding of their niche signals have not yet been achieved. Using a CML-like mouse model of myeloproliferative disease, we demonstrate that CML LICs can be divided into CD25⁺FcεRIα^- Lineage marker (Lin)^- Sca-1⁺c-Kit⁺ (F^-LSK) cells and CD25 ^-F^-LSK cells. The CD25⁺F^-LSK cells had multilineage differentiation capacity, with a preference toward cytokine-producing mast cell commitment. Although cells interconverted between CD25^-F^-LSK and CD251F2LSK status, the CD25 ⁺F^-LSK cells exhibited higher LIC capacity. Our findings suggest that interleukin-2 derived from the microenvironment and CD25 expressed on CML LICs constitute a novel signaling axis. The high levels of CD25 expression in the CD34⁺CD38^- fraction of human CML cells indicate that CD25⁺ LICs constitute an "LIC-derived niche" that could be preferentially targeted in therapy for CML.