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Daniel Starczynowski: Microbial metabolite drives ageing-related clonal hematopoiesis via ALPK1

Daniel Starczynowski/LinkedIn

Apr 24, 2025, 15:09

Daniel Starczynowski: Microbial metabolite drives ageing-related clonal hematopoiesis via ALPK1

Daniel Starczynowski, Director of Advanced Leukemia Therapies and Research Center at Cincinnati Children’s Hospital Medical Center, posted on LinkedIn, about recent paper he and his colleagues co-authored:

“Thrilled to share our latest research out today in Nature: ‘Microbial metabolite drives ageing-related clonal hematopoiesis via ALPK1′. We uncover how age-related changes in gut health and the microbiome promote pre-leukemic stem cell expansion and increase disease risk:

Big congratulations to lead author Puneet Agarwal for spearheading this study! We’re deeply grateful to collaborators Paresh Vyas, John Byrd, Jessica Galloway-Pena, Kenneth Setchell, Xuehengng Zhao, Avery Sampson, and our supporters at the NIH, The Edward P Evans Foundation, CancerFreeKids.

What drives the expansion of pre-leukemic cells as we age? Our gut might hold the answer. Using a mouse model of pre-leukemia (CHIP CCUS), we found that gut injury—common with aging—directly promotes the expansion and function of pre-leukemic cells.

Aging impairs gut integrity and increases gram-negative bacteria. We showed that gram-negative bacteria – and specifically ADP-heptose, a sugar metabolite they secrete – are required for pre-leukemic expansion.

ADP-heptose activates ALPK1, triggering the formation of cytoplasmic “TIFAsome” signaling structures in pre-leukemic cells. We found that circulating ADP-heptose levels are elevated in aged individuals, as well as those with CHIP and MDS—and closely track with advancing age.

To detect this in circulation, we developed a TIFAsome assay, enabling direct measurement of ADP-heptose bioactivity in plasma:

To identify therapeutic targets, we performed a screen across ALPK1 effectors—and found that UBE2N is essential for ADP-heptose-induced TIFAsome formation and pre-leukemic growth.

In summary, age-related gut changes and ADP-heptose derived from certain bacteria promote pre-leukemic cell expansion through ALPK1/TIFAsome signaling. Targeting the ADP-heptose–ALPK1 axis or improving gut health could be a novel strategy to prevent age-related blood cancers.

Grateful to the Nature editors and reviewers for the valuable guidance. Special thanks to our fantastic team in the Starczynowski Lab and at Cincinnati Children’s Hospital and UC Cancer Center.”

Title: Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1

Authors: Puneet Agarwal, Daniel T. Starczynowski, et al.

Journal: Nature, April 2025

Daniel Starczynowski: Microbial metabolite drives ageing-related clonal hematopoiesis via ALPK1