Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche
Open accessAbstract
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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In murine models of MPN and AML, the hematological malignancy created neuropathic changes in the BM niche, which affected the activity of MSCs and altered the function of the HSC niche, leading to downregulated expression of many HSC-retention factors, including CXCL12 and SCF.
“In murine models of MPN 80 and AML, 81 the hematological malignancy created neuropathic changes in the BM niche, which affected the activity of MSCs and altered the function of the HSC niche, in particular leading to downregulated expression of many HSC-retention factors, including CXCL12 and SCF, indicating loss of hematopoiesis support.”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [81]
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- Authors
- Hanoun, M., Zhang, D., Mizoguchi, T., Pinho, S., Pierce, H., Kunisaki, Y., Lacombe, J., Armstrong, S. A., Dührsen, U., & Frenette, P. S.
- Affiliations
- Albert Einstein College of Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Essen University Hospital (DE)
- Corresponding author
- Frenette, Paul S.
- ORCID
- Venue
- Cell stem cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 15
- Issue
- 3
- Pages
- 365-375
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4156919
- OpenAlex
- W2044703599
- Cited by
- 381
- References
- 36
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 26 · 2023: 36 · 2022: 31 · 2021: 42 · 2020: 43 · 2019: 28 · 2018: 38 · 2017: 39 · 2016: 30 · 2015: 28 · 2014: 4
- FWCI
- 23.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (26893185)
- National Heart, Lung, and Blood Institute (R01HL116340, HL097819, HL116340, R01HL097819)
- National Cancer Institute (#CA66996, CA140575, R01CA140575, P30CA008748, P30CA013330, P01CA066996)
- National Institute of General Medical Sciences (GM007491, T32GM007491)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056638, DK056638)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- acute myeloid leukemia, sympathetic neuropathy, hematopoietic niche, MLL-AF9, adrenergic signaling, beta2-adrenergic receptor, beta3-adrenergic receptor, osteogenic differentiation, leukemogenesis, microenvironment
- MeSH terms
- Animals, Autonomic Nervous System Diseases, Bone Marrow Cells, Hematopoietic Stem Cells, Humans, Mice, Inbred C57BL, Osteoblasts, Signal Transduction, Leukemia, Myeloid, Acute, Stromal Cells, Receptors, Adrenergic, beta-2, Cell Lineage, Cell Proliferation, Green Fluorescent Proteins, Stem Cell Niche, Mesenchymal Stem Cells, Carcinogenesis, Nestin
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