Journal
BLOOD
Volume 123, Issue 16, Pages 2540-2549Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-07-517847
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Funding
- Tenure-Track Program at the Sakaguchi Laboratory
- MEXT
- Grants-in-Aid for Scientific Research [23591369, 11J04561, 23689049, 26461170, 26221309, 25118724] Funding Source: KAKEN
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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(+) Fc epsilon RI alpha(-) 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 CD25(+)F(-)LSK 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.
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