A Stress Response Pathway That Enhances Hematopoietic Stem Cell Longevity Promotes Acute Myeloid Leukemia Growth and Progression

Aging is the single biggest risk factor for the development of cancer. This association has historically been attributed to the fact that rate limiting genetic mutations accumulate over time. However, many other hallmarks of aging can convey selective advantages that may ultimately promote the development of cancer. We recently discovered that aging hematopoietic stem cells (HSCs) activate Heat shock factor 1 (HSF1), a key transcriptional regulator that dynamically remodels the protein homeostasis (proteostasis) network upon acute and chronic proteotoxic stress. HSF1 activation promotes HSC fitness and proteostasis maintenance during aging. Several high-risk leukemogenic mutations tend to arise disproportionately in older adults, but whether HSF1 confers fitness advantages to acute myeloid leukemia (AML) cells is untested. We found that HSF1 is highly expressed across multiple human AML cell lines harboring distinct mutational profiles, and that it is readily activated in response to stress. CRISPR-Cas9 mediated deletion of HSF1 significantly reduced AML cell growth and proliferation in vitro. Furthermore, HSF1-deficiency severely impaired AML progression and significantly extended survival within xenograft models in vivo. Finally, in line with its role in mitigating proteotoxic stress, we determined that HSF1 conferred human AML cells with significant therapeutic resistance to proteasome inhibitors. HSF1-deficient AML cells treated with the proteasome inhibitor carfilzomib exhibited severely reduced proliferation and increased cell death. This study reveals that age-associated stress response pathways that promote HSC fitness can inadvertently support AML growth and confer therapeutic resistance. Identifying connections between molecular and physiological changes in aging HSCs with the emergence of leukemia holds potential for uncovering new therapeutic opportunities to prevent/treat leukemia by targeting underlying age-related changes in stem cell proteostasis.

No relevant conflicts of interest to declare.