Differential regulation of myeloid leukemias by the bone marrow microenvironment
Daniela S. Krause,Keertik Fulzele,Andre Catic,Chia Chi Sun,David Dombkowski,Michael P. Hurley,Sanon Lezeau,Eyal C. Attar,Joy Y. Wu,Herbert Y. Lin,Paola Divieti-Pajevic,Robert P. Hasserjian,Ernestina Schipani,Richard A. Van Etten,David T. Scadden +14 more
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TLDR
It is demonstrated that LSC niches in CML and AML are distinct and suggested that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.Abstract:
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.read more
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Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment.
Paolo Bernasconi,Oscar Borsani +1 more
TL;DR: It has been well established that the leukemic population may misinterpret niche-derived signals and remodel the niche, providing a shelter to AML cells and protecting them from the cytotoxic effects of chemoradiotherapy, and the removal of LSCs from the BM niche and the promotion of normal HSC engraftment should be the primary goals in antileukemic research.
Journal ArticleDOI
Bioengineering of Humanized Bone Marrow Microenvironments in Mouse and Their Visualization by Live Imaging.
TL;DR: Using two-photon microscopy, this work can live-image structures in situ in situ at the single-cell resolution, providing a powerful new tool for the functional characterization of the human BM microenvironment and its role in regulating normal and malignant hematopoiesis.
Journal ArticleDOI
Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia.
Rahul Kumar,Raquel S. Pereira,Costanza Zanetti,Valentina R. Minciacchi,Maximilian Merten,Melanie Meister,Julian Niemann,Marina S. Dietz,Nina Rüssel,Frank Schnütgen,Minori Tamai,Koshi Akahane,Takeshi Inukai,Thomas Oellerich,Hans Michael Kvasnicka,Heike Pfeifer,Franck E. Nicolini,Mike Heilemann,Richard A. Van Etten,Daniela S. Krause +19 more
TL;DR: Interactions with ECM proteins via the integrin β3/ILK-mediated signaling pathway in BCR-ABL1 T315I+ cells differentially and specifically influence leukemia progression are suggested.
Journal ArticleDOI
ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression.
Dan Huang,Guohuan Sun,Xiaoxin Hao,Xiaoxiao He,Zhaofeng Zheng,Chiqi Chen,Zhuo Yu,Li Xie,Shihui Ma,Ligen Liu,Bo O. Zhou,Hui Cheng,Junke Zheng,Tao Cheng +13 more
TL;DR: A role of niche-specific SEVs in cancer development is demonstrated and targeting ANGPTL2-SEVs from ECs might be a potential strategy to interfere certain types of AML.
Journal ArticleDOI
The Hematopoietic Bone Marrow Niche Ecosystem
Julia Fröbel,Theresa Landspersky,Gulce Percin,Christina Schreck,Susann Rahmig,Alessandro Ori,Daniel Nowak,Marieke A.G. Essers,Claudia Waskow,Claudia Waskow,Claudia Waskow,Robert A.J. Oostendorp +11 more
TL;DR: The bone marrow microenvironment, also called the BM niche, is essential for the maintenance of fully functional blood cell formation (hematopoiesis) throughout life as discussed by the authors, and changes in BM niche composition (ecosystem) and structure (remodeling) modulate activation of HSCs.
References
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Journal ArticleDOI
Osteoblastic cells regulate the haematopoietic stem cell niche
Laura M. Calvi,Gregor B. Adams,Kathryn W. Weibrecht,Jonathan M. Weber,David P. Olson,M. C. Knight,Roderick P. Martin,Ernestina Schipani,P. Divieti,F. R. Bringhurst,Laurie A. Milner,Henry M. Kronenberg,David T. Scadden +12 more
TL;DR: Osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation.
Journal ArticleDOI
Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome
TL;DR: It is demonstrated that P210bcr/abl expression can induce chronic myelogenous leukemia and retrovirus-mediated expression of the protein provides a murine model system for further analysis of the disease.
Journal ArticleDOI
Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.
Andrei V. Krivtsov,David Twomey,David Twomey,Zhaohui Feng,Matthew C. Stubbs,Yingzi Wang,Joerg Faber,Jason E. Levine,Jing Wang,William C. Hahn,William C. Hahn,D. Gary Gilliland,D. Gary Gilliland,Todd R. Golub,Todd R. Golub,Scott A. Armstrong +15 more
TL;DR: It is shown that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme.
Journal ArticleDOI
Targeting of CD44 eradicates human acute myeloid leukemic stem cells
TL;DR: It is demonstrated that absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted, and mechanisms underlying this eradication included interference with transport to stem cell–supportive microenvironmental niches and alteration of AML-LSC fate.
Journal ArticleDOI
Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.
Jodie L. Babitt,Franklin W. Huang,Diedra M. Wrighting,Yin Xia,Yisrael Sidis,Tarek A. Samad,Jason A. Campagna,Raymond T. Chung,Alan L. Schneyer,Clifford J. Woolf,Nancy C. Andrews,Nancy C. Andrews,Herbert Y. Lin +12 more
TL;DR: Hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability, and BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemoJuvelin and blunted in Hfe2−/− hepatocytes.