ALWAYS STRESSED BUT NEVER EXHAUSTED: HOW STEM CELLS IN MYELOID NEOPLASMS AVOID EXTINCTION IN INFLAMMATORY CONDITIONS

Chronic or recurrent episodes of acute inflammation cause attrition of normal hematopoietic stem cells (HSCs) that can lead to hematopoietic failure, but they drive progression in myeloid malignancies and their precursor clonal hematopoiesis (CH). Mechanistic parallels exist between hematopoiesis in chronic inflammation and the continuously increased proliferation of myeloid malignancies, particularly myeloproliferative neoplasms (MPNs). The ability to enter dormancy, a state of deep quiescence characterized by low oxidative phosphorylation, low glycolysis, reduced protein synthesis, and increased autophagy is central to the preservation of long term HSCs and likely MPN SCs. The metabolic features of dormancy resemble those of diapause, a state of arrested embryonic development triggered by adverse environmental conditions. To outcompete their normal counterparts in the inflammatory MPN environment, MPN SCs co-opt mechanisms used by HSCs to avoid exhaustion, including signal attenuation by negative regulators, insulation from activating cytokine signals, anti-inflammatory signaling, and epigenetic reprogramming. We propose that new therapeutic strategies may be derived from conceptualizing myeloid malignancies as an ecosystem out of balance, where residual normal and malignant hematopoietic cells interact in multiple ways, only few of which have been characterized in detail. Disrupting MPN SC insulation to overcome dormancy, interfering with aberrant cytokines circuits that favor MPN cells and directly boosting residual normal HSCs are potential strategies to tip the balance in favor of normal hematopoiesis. While eradicating the malignant cell clones remains the goal of therapy, this may be a more attainable objective in the short term.