Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell Niche

Maher Hanoun, Dachuan Zhang, Toshihide Mizoguchi, Sandra I. Pinho, Halley Pierce, Yuya Kunisaki, Julie Lacombe, Scott A. Armstrong, Ulrich Dührsen, Paul S. Frenette

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)365-375
Number of pages11
JournalCell Stem Cell
Volume15
Issue number3
DOIs
StatePublished - 2014

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Stem Cell Niche
Hematopoietic Stem Cells
Mesenchymal Stromal Cells
Acute Myeloid Leukemia
Sympathetic Nervous System
Neoplasms
Bone Marrow
Nestin
Adrenergic Agents
Adrenergic Receptors

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell Niche. / Hanoun, Maher; Zhang, Dachuan; Mizoguchi, Toshihide; Pinho, Sandra I.; Pierce, Halley; Kunisaki, Yuya; Lacombe, Julie; Armstrong, Scott A.; Dührsen, Ulrich; Frenette, Paul S.

In: Cell Stem Cell, Vol. 15, No. 3, 2014, p. 365-375.

Research output: Contribution to journalArticle

Hanoun, M, Zhang, D, Mizoguchi, T, Pinho, SI, Pierce, H, Kunisaki, Y, Lacombe, J, Armstrong, SA, Dührsen, U & Frenette, PS 2014, 'Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell Niche', Cell Stem Cell, vol. 15, no. 3, pp. 365-375. https://doi.org/10.1016/j.stem.2014.06.020
Hanoun, Maher ; Zhang, Dachuan ; Mizoguchi, Toshihide ; Pinho, Sandra I. ; Pierce, Halley ; Kunisaki, Yuya ; Lacombe, Julie ; Armstrong, Scott A. ; Dührsen, Ulrich ; Frenette, Paul S. / Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell Niche. In: Cell Stem Cell. 2014 ; Vol. 15, No. 3. pp. 365-375.
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AU - Pierce, Halley

AU - Kunisaki, Yuya

AU - Lacombe, Julie

AU - Armstrong, Scott A.

AU - Dührsen, Ulrich

AU - Frenette, Paul S.

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AB - 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.

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