Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia

Aging is the primary risk factor for clonal hematopoiesis and the development of hematologic malignancies (1-5), yet the selective pressures that shape stem cell behavior and clonal expansion during aging remain poorly defined. Here, we identify proteostasis stress as a central driver of hematopoietic stem cell (HSC) aging and clonal evolution. We show that Heat shock factor 1 (Hsf1) is activated in aging HSCs to preserve proteostasis and sustain self-renewal. However, this physiological, age-associated adaptive mechanism is co-opted by pre-leukemic Dnmt3a-mutant HSCs to resist proteostasis and inflammatory stress required to fuel clonal expansion during aging. In the context of co-occurring Dnmt3a and Nras mutations, which are frequently observed in human acute myeloid leukemia (AML) (6-13), mutant HSCs and progenitors exhibit heightened dependence on Hsf1 for expansion, malignant transformation and disease progression. Loss of Hsf1, or disruption of proteostasis, impairs expansion of mutant progenitors, delays leukemia onset, and prolongs survival. Together, these findings reveal proteostasis as a key constraint in the aging hematopoietic system that imposes a selective bottleneck. Hsf1 activation enables both physiological adaptation in aging stem cells and pathological clonal outgrowth in pre-leukemic and leukemic states, establishing proteostasis control as a pivotal mechanism linking stem cell aging to clonal hematopoiesis and malignancy.