Leveraging HSF1 Attenuation to Transform Clonal Hematopoiesis into Beneficial Hematopoiesis

Case Western Reserve University, Cleveland OH

Investigators

Abstract

Project Summary_Abstract Age-related clonal hematopoiesis (CH), characterized by the enhanced fitness of hematopoietic stem/progenitor cells (HSPCs) carrying somatic mutations, is associated with increased risks of developing hematological malignancies such as myelodysplastic syndrome or acute myeloid leukemia (AML), as well as solid tumors, cardiovascular disease, chronic obstructive pulmonary disease, and severe symptoms during certain microbial infections. While CH is often linked to unfavorable outcomes, it also corelates with beneficial conditions, including a reduced risk of Alzheimer disease, an increase in the graft-versus-leukemia effect, and preserved T-cell immunity. The central question arises: Can we sustain the heightened self-renewal of HSPCs associated with CH while preventing its progression? Heat shock transcription factor 1 (HSF1) plays a pivotal role in cellular stress responses, metabolism, aging, and cancer. Our recent research, involving genetic knockout and pharmacological degradation of HSF1, has highlighted its critical role in maintaining AML stem cells while being nonessential in normal HSPCs. Utilizing newly generated DNMT3a/HSF1 and TET2/HSF1 double knockout mouse models, we observed that the deletion of HSF1 along with Tet2 or Dnmt3a sustains or enhances HSPC engraftment and maintains balanced lineage commitment. Notably, these double knockout mice exhibit a reduced incidence of myeloid or lymphoid neoplasms compared to counterparts with sole TET2 or DNMT3a deleted. Gene set enrichment analysis revealed an upregulation in mitochondrial oxidative phosphorylation (OXPHOS) and/or glycolysis pathways in DNMT3aHSF1 or TET2/HSF1 doubly deleted HSPCs compared to those with sole DNMT3a or TET2 deletions. Additionally, we found that HSF1 protein expression is higher in bone marrow immature cells compared to mature cells, upregulated in TET2 and DNMT3a deleted bone marrow cells, and decreased during aging, suggesting a potential protective role in maintaining HSPC function in CH. The observed ability of HSF1 deletion to sustain or enhance HSPC self- renewal, maintain balanced lineage commitment, and prevent CH progression underscores its appeal as a target. Based on these preliminary findings, we hypothesize that modulating HSF1 may hold the key to transforming detrimental CH into a state favoring normal hematopoiesis while simultaneously preventing CH progression. We aim to address the following two fundamental questions: 1) how DNMT3aHSF1 or TET2HSF1 doubly deleted HSPC function is maintained or enhanced with upregulated mitochondrial function, considering the consensus that adult HSPC homeostasis relies on glycolysis; and 2) how HSF1 deletion prevents CH progression and the impact of HSF1 nuclear degrader in CH. These findings have the potential to significantly impact the development of targeted interventions, preserving normal hematopoiesis and impeding CH progression.