Abstract
Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM)1 and may be the cause of relapse following chemotherapy2. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling6 and plays a part in maintenance of CML LSCs7, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell–specific activation of the parathyroid hormone (PTH) receptor8,9 attenuates BCR-ABL1 oncogene–induced CML-like myeloproliferative neoplasia (MPN)10 but enhances MLL-AF9 oncogene–induced AML11 in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.
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Acknowledgements
The authors thank A. Legedza and D. Neuberg for advice on statistical analysis and H.-H. Chen for helpful discussions. This work was supported by grants K08 CA138916-02 and T32 CA009216 to D.S.K., grant AR060221 to K.F. and P.D.P., grant R21AR060689 to E.S., grants R01 CA090576 and R01 HL089747 to R.A.V., grants R01 HL044851 and R01 CA148180 and a grant from The Ellison Medical Foundation to D.T.S. A.C. was supported by US National Institute on Aging grant K01AG036744.
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D.S.K. designed and carried out all experiments, analyzed the data and wrote the manuscript. K.F. performed immunohistochemistry studies. C.C.S. performed studies on active TGF-β1, and D.D. sorted cells by flow cytometry. S.L. and M.P.H. helped with mouse experiments. R.P.H. acted as the blinded hematopathologist. R.A.V. provided space, reagents and equipment for Southern blotting, analyzed data and critically reviewed and cowrote the manuscript. D.T.S. supervised the project, analyzed data and cowrote the manuscript. Other co-authors A.C., E.A., J.Y.W., H.Y.L., P.D.-P., and E.S. acted as advisors, provided critical reagents and reviewed the manuscript.
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Krause, D., Fulzele, K., Catic, A. et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med 19, 1513–1517 (2013). https://doi.org/10.1038/nm.3364
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DOI: https://doi.org/10.1038/nm.3364
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