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

Maher Hanoun1, Dachuan Zhang1, Toshihide Mizoguchi1

  • 1Ruth 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.

Cell Stem Cell
|July 15, 2014
PubMed

Insights

Sympathetic nerve damage in acute myelogenous leukemia (AML) bone marrow promotes cancer infiltration. This neuropathy disrupts the healthy stem cell niche, favoring leukemia development and altering mesenchymal stem and progenitor cells (MSPCs).

Area of Science:

  • Hematology
  • Stem Cell Biology
  • Neuroscience

Background:

  • Perivascular mesenchymal stem and progenitor cells (MSPCs) are crucial for maintaining the hematopoietic stem cell (HSC) niche.
  • The interaction between acute myelogenous leukemia (AML) stem cells and their microenvironment is not well understood.

Purpose of the Study:

  • To investigate the influence of the sympathetic nervous system (SNS) on AML progression and bone marrow infiltration.
  • To explore how AML affects the cellular composition and function of the HSC niche.

Main Methods:

  • Utilized an MLL-AF9 murine model of AML.
  • Investigated the role of sympathetic neuropathy and adrenergic signaling in leukemogenesis.
  • Analyzed changes in Nestin(+) and NG2(+) niche cells and MSPC differentiation.

Main Results:

  • Sympathetic nervous system (SNS) neuropathy unexpectedly promotes leukemic bone marrow infiltration in AML.
  • AML development disrupts SNS nerves and quiescent Nestin(+) niche cells.
  • This disruption leads to an expansion of osteoblastic-primed MSPCs at the expense of HSC-maintaining NG2(+) periarteriolar niche cells.
  • Leukemogenesis is promoted by adrenergic signaling via the β2 adrenergic receptor on stromal cells.

Conclusions:

  • Sympathetic neuropathy may be a mechanism by which AML co-opts the bone marrow microenvironment.
  • Mesenchymal niches may have distinct roles for malignant versus healthy hematopoietic stem cells.

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