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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\n                  <jats:italic>Dnmt3a<\/jats:italic>\n                  -mutant HSCs to resist proteostasis and inflammatory stress required to fuel clonal expansion during aging. In the context of co-occurring\n                  <jats:italic>Dnmt3a<\/jats:italic>\n                  and\n                  <jats:italic>Nras<\/jats:italic>\n                  mutations, which are frequently observed in human acute myeloid leukemia (AML) (\n                  <jats:italic>6\u201313<\/jats:italic>\n                  ), mutant HSCs and progenitors exhibit heightened dependence on Hsf1 for expansion, malignant transformation and disease progression. Loss of\n                  <jats:italic>Hsf1<\/jats:italic>\n                  , 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.\n                <\/jats:p>","DOI":"10.1101\/2025.11.27.690982","type":"posted-content","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T02:05:46Z","timestamp":1764641146000},"source":"Crossref","is-referenced-by-count":1,"title":["Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia"],"prefix":"10.64898","author":[{"given":"Fanny J.","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle K.","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen C.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-You","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arukshita","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjian","family":"Cen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Jean","family":"Sunshine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Magee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.J.","family":"Signer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025120217001230000_2025.11.27.690982v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2006.11.019"},{"key":"2025120217001230000_2025.11.27.690982v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.01.036"},{"key":"2025120217001230000_2025.11.27.690982v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2304431"},{"issue":"6","key":"2025120217001230000_2025.11.27.690982v1.4","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1182\/blood.2022017933","article-title":"Hematopoietic stem cell aging and leukemia transformation","volume":"142","year":"2023","journal-title":"Blood"},{"key":"2025120217001230000_2025.11.27.690982v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2019.04.006"},{"key":"2025120217001230000_2025.11.27.690982v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng.788"},{"key":"2025120217001230000_2025.11.27.690982v1.7","doi-asserted-by":"crossref","unstructured":"J. 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