Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin-beta receptor signaling.
- Yale University, United States
- Korea University, Republic of Korea
- University of California, San Francisco, United States
Abstract
Acute lymphoblastic and myeloblastic leukemias (ALL and AML) have been known to modify the bone marrow microenvironment and disrupt non-malignant hematopoiesis. However, the molecular mechanisms driving these alterations remain poorly defined. Using mouse models of ALL and AML, here we show that leukemic cells turn-off lymphopoiesis and erythropoiesis shortly after colonizing the bone marrow. ALL and AML cells express lymphotoxin-a1b2 and activate LTbR signaling in mesenchymal stem cells (MSCs), which turns off IL7 production and prevents non-malignant lymphopoiesis. We show that the DNA damage response pathway and CXCR4 signaling promote lymphotoxin-a1b2 expression in leukemic cells. Genetic or pharmacologic disruption of LTbR signaling in MSCs restores lymphopoiesis but not erythropoiesis, reduces leukemic cell growth, and significantly extends the survival of transplant recipients. Similarly, CXCR4 blocking also prevents leukemia-induced IL7 downregulation, and inhibits leukemia growth. These studies demonstrate that acute leukemias exploit physiological mechanisms governing hematopoietic output as a strategy for gaining competitive advantage.
Data availability
Accession number to RNA expression data were deposited in NCBI (GSE221243)
Article and author information
Author details
Joao Pedro Pereira
Funding
NIH Office of the Director (R01AI113040)
- Joao Pedro Pereira
NIH Office of the Director (R21AI133060)
- Joao Pedro Pereira
NIH Office of the Director (R35CA197628)
- Marcus Müschen
NIH Office of the Director (R01AI164692)
- Marcus Müschen
NIH Office of the Director (R21AI146648)
- Marcus Müschen
NIH Office of the Director (T32 DK007356)
- Xing Feng
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were maintained under specific pathogen-free conditions at the Yale Animal Resources Center and were used according to the protocol approved by the Yale University Institutional Animal Care and Use Committee. (2022-11377).
Copyright
© 2023, Feng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin-beta receptor signaling.
eLife 12:e83533.
https://doi.org/10.7554/eLife.83533
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