title: Differential regulation of myeloid leukemias by the bone marrow microenvironment.
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) and may be the cause of relapse following chemotherapy. 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 remodeling and plays a part in maintenance of CML LSCs, 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) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML 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.
authors.affiliation: 1] Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [3] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [4] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Krause
authors.forename: Keertik
authors.initials: K
authors.lastname: Fulzele
authors.forename: André
authors.initials: A
authors.lastname: Catic
authors.forename: Chia Chi
authors.initials: CC
authors.lastname: Sun
authors.forename: David
authors.initials: D
authors.lastname: Dombkowski
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hurley
authors.forename: Sanon
authors.initials: S
authors.lastname: Lezeau
authors.forename: Eyal
authors.initials: E
authors.lastname: Attar
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Wu
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.forename: Paola
authors.initials: P
authors.lastname: Divieti-Pajevic
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hasserjian
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D016313:Genes, abl; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010281:Parathyroid Hormone / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D010281:Parathyroid Hormone; D053773:Transforming Growth Factor beta1