{"doi":"10.1101/2025.11.27.690982","title":"Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559621,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1460902,"name":"Michelle Le","orcid":"0000-0002-9393-0922","position":1,"is_corresponding":false},{"id":669834,"name":"Helen C. Wang","orcid":"0000-0001-8887-1799","position":2,"is_corresponding":false},{"id":362435,"name":"Wei Yang","orcid":"0000-0001-8162-033X","position":3,"is_corresponding":false},{"id":383795,"name":"Huan‐You Wang","orcid":"0000-0002-6777-8963","position":4,"is_corresponding":false},{"id":1461454,"name":"Arukshita Tiwari","orcid":null,"position":5,"is_corresponding":false},{"id":815217,"name":"Xinjian Cen","orcid":"0000-0002-1663-1347","position":6,"is_corresponding":false},{"id":278167,"name":"Mary Jean Sunshine","orcid":"0000-0002-2188-7881","position":7,"is_corresponding":false},{"id":571161,"name":"Jeffrey A. Magee","orcid":"0000-0002-0766-4200","position":8,"is_corresponding":false},{"id":278171,"name":"Robert Signer","orcid":"0000-0003-3286-1334","position":9,"is_corresponding":false},{"id":351717,"name":"Fanny Zhou","orcid":"0000-0001-8260-6775","position":0,"is_corresponding":true}],"reference_count":193,"raw_metadata":null,"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41383784","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}