title: Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche.
abstract: Perivascular mesenchymal stem and progenitor cells (MSPCs) are critical for forming a healthy hematopoietic stem cell (HSC) niche. However, the interactions and influence of acute myelogenous leukemia (AML) stem cells with the microenvironment remain largely unexplored. We have unexpectedly found that neuropathy of the sympathetic nervous system (SNS) promotes leukemic bone marrow infiltration in an MLL-AF9 AML model. Development of AML disrupts SNS nerves and the quiescence of Nestin(+) niche cells, leading to an expansion of phenotypic MSPCs primed for osteoblastic differentiation at the expense of HSC-maintaining NG2(+) periarteriolar niche cells. Adrenergic signaling promoting leukemogenesis is transduced by the β2, but not β3, adrenergic receptor expressed on stromal cells of leukemic bone marrow. These results indicate that sympathetic neuropathy may represent a mechanism for the malignancy in order to co-opt the microenvironment and suggest separate mesenchymal niche activities for malignant and healthy hematopoietic stem cells in the bone marrow.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Maher
authors.initials: M
authors.lastname: Hanoun
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Dachuan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mizoguchi
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinho
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Halley
authors.initials: H
authors.lastname: Pierce
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kunisaki
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Lacombe
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, Memorial Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Department of Hematology, University Hospital, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: paul.frenette@einstein.yu.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000209:etiology* / Q000473:pathology*; D001854:Bone Marrow Cells / Q000473:pathology; D063646:Carcinogenesis / Q000473:pathology; D019070:Cell Lineage; D049109:Cell Proliferation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000473:pathology; D008810:Mice, Inbred C57BL; D064231:Nestin / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D064231:Nestin; D018343:Receptors, Adrenergic, beta-2; D049452:Green Fluorescent Proteins