JMML tumor cells disrupt normal hematopoietic stem cells by imposing inflammatory stress through overproduction of IL-1β
| Autor: | Kevin D. Bunting, Mignon L. Loh, Yuhan Yan, Qianjin Li, Chao Chen, Elliot Stieglitz, Cheng-Kui Qu, Lei Dong |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Myeloid
Pediatric Cancer Interleukin-1beta Juvenile Biology Regenerative Medicine Proinflammatory cytokine Mice Rare Diseases Bone Marrow Stem Cell Research - Nonembryonic - Human Receptors medicine Tumor Microenvironment Animals Humans 2.1 Biological and endogenous factors Progenitor cell Aetiology Myeloproliferative neoplasm Cancer Inflammation Pediatric Transplantation Myeloproliferative Disorders Leukemia Juvenile myelomonocytic leukemia Inflammatory and immune system Receptors Interleukin-1 Myelomonocytic Hematology medicine.disease Hematopoietic Stem Cells Stem Cell Research Stimulus Report Haematopoiesis medicine.anatomical_structure Orphan Drug Leukemia Myelomonocytic Juvenile Cancer research Stem Cell Research - Nonembryonic - Non-Human Bone marrow Stem cell Interleukin-1 |
| Zdroj: | Blood advances, vol 6, iss 1 Blood Advances |
| Popis: | Key Points Normal hematopoiesis is suppressed by JMML tumor cells as a result of the aberrant activation and exhaustion of stem cells.JMML cells impose inflammatory stress on normal stem cells by over production of IL-1β. 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, T NF-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. |
| Databáze: | OpenAIRE |
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