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Differential regulation of myeloid leukemias by the bone marrow microenvironment.
- Source :
-
Nature medicine [Nat Med] 2013 Nov; Vol. 19 (11), pp. 1513-7. Date of Electronic Publication: 2013 Oct 27. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Female
Genes, abl
Humans
Leukemia, Myeloid genetics
Male
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Oncogene Proteins, Fusion genetics
Parathyroid Hormone metabolism
Signal Transduction
Stem Cell Niche
Transforming Growth Factor beta1 metabolism
Tumor Microenvironment
Bone Marrow metabolism
Bone Marrow pathology
Leukemia, Myeloid metabolism
Leukemia, Myeloid pathology
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 19
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 24162813
- Full Text :
- https://doi.org/10.1038/nm.3364