JMML tumor cells disrupt normal hematopoietic stem cells by imposing inflammatory stress through overproduction of IL-1β.
Yuhan YanLei DongChao ChenKevin D BuntingQianjin LiElliot StieglitzMignon L LohCheng-Kui QuPublished in: Blood advances (2021)
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 (Ptpn11E76K) 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 Ptpn11E76K/+ 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 Ptpn11E76K/+ MPN cells produced excessive IL-1β, but not IL-6, TNF-α, IFN-γ, IL-1α, or other inflammatory cytokines. Depletion of the IL-1β receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11E76K/+/IL-1R-/- double mutant mice. These findings suggest IL-1β signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.
Keyphrases
- bone marrow
- stem cells
- induced apoptosis
- wild type
- cell cycle arrest
- mesenchymal stem cells
- rheumatoid arthritis
- single cell
- high fat diet induced
- acute myeloid leukemia
- adipose tissue
- dendritic cells
- type diabetes
- neuropathic pain
- cell proliferation
- immune response
- young adults
- insulin resistance
- low grade
- spinal cord
- physical activity
- body mass index
- weight loss
- pluripotent stem cells