Journal
BLOOD ADVANCES
Volume 6, Issue 1, Pages 200-206Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2021005089
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Funding
- National Heart, Lung, and Blood Institute [HL130995]
- National Cancer Institute [CA255831]
- Winship Cancer Institute Invest$ Pilot grant
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Suppression of normal blood cell development is observed in juvenile myelomonocytic leukemia (JMML), impacting therapeutic outcomes. In a study, the most common mutation found in JMML (Ptpn11(E76K)) was induced specifically in the myeloid lineage, leading to the development of a JMML-like myeloproliferative neoplasm (MPN). Importantly, hematopoietic stem cells (HSCs) in the same bone marrow microenvironment were aberrantly activated and differentiated, resulting in loss of quiescence and exhaustion. Further experiments showed that JMML/MPN cells accelerated differentiation in normal hematopoietic stem/progenitor cells. Excessive production of IL-1 beta by Ptpn11(E76K/+) MPN cells was identified and depletion of the IL-1 beta receptor restored HSC quiescence and rescued them from exhaustion, suggesting IL-1 beta signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.
Development of normal blood cells is often suppressed in juvenile myelomonocytic leukemia (JMML), a myeloproliferative neoplasm (MPN) of childhood, causing complications and impacting therapeutic outcomes. However, the mechanism underlying this phenomenon remains uncharacterized. To address this question, we induced the most common mutation identified in JMML (Ptpn11(E76K)) specifically in the myeloid lineage with hematopoietic stem cells (HSCs) spared. These mice uniformly developed a JMML-like MPN. Importantly, HSCs in the same bone marrow (BM) microenvironment were aberrantly activated and differentiated at the expense of self-renewal. As a result, HSCs lost quiescence and became exhausted. A similar result was observed in wild-type (WT) donor HSCs when co-transplanted with Ptpn11(E76K/+) BM cells into WT mice. Co-culture testing demonstrated that JMML/MPN cells robustly accelerated differentiation in mouse and human normal hematopoietic stem/progenitor cells. Cytokine profiling revealed that Ptpn11(E76K/+) MPN cells produced excessive IL-1 beta, but not IL-6, T NF-alpha, IFN-gamma, IL-1 alpha, or other inflammatory cytokines. Depletion of the IL-1 beta receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11(E76K/+/IL-1R-/-) double mutant mice. These findings suggest IL-1 beta signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.
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