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Differential regulation of myeloid leukemias by the bone marrow microenvironment

ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/nm.3364

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  • Title:
    Differential regulation of myeloid leukemias by the bone marrow microenvironment
  • Author: Krause, Daniela S ; Fulzele, Keertik ; Catic, Andre ; Sun, Chia Chi ; Dombkowski, David ; Hurley, Michael P ; Lezeau, Sanon ; Attar, Eyal ; Wu, Joy Y ; Lin, Herbert Y ; Divieti-Pajevic, Paola ; Hasserjian, Robert P ; Schipani, Ernestina ; Van Etten, Richard A ; Scadden, David T
  • Description: Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSC) 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 chemotherapy.2 Targeting the niche is a novel strategy to eliminate persistent and drug-resistant LSC. CD443,4 and IL-65 have been implicated previously in the LSC niche. Transforming growth factor (TGF)-β1 is released during bone remodeling6 and plays a role 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-induced CML-like myeloproliferative neoplasia (MPN)10 but enhances MLL-AF9-induced AML11 in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSC. PTH treatment caused a 15-fold decrease in LSCs in wildtype mice with CML-like MPN, and reduced engraftment of immune deficient mice with primary human CML cells. These results demonstrate that LSC niches in chronic and acute myeloid leukemias are distinct, and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSC, a prerequisite for the cure of CML.
  • Creation Date: 2013
  • Language: English
  • Identifier: ISSN: 1078-8956
    EISSN: 1546-170X
    DOI: 10.1038/nm.3364
  • Source: ProQuest Central
    Harvard University Library DASH
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