Study Finds Link Between Gut Health and Leukemia Risk

Researchers from the Cincinnati Children’s Hospital Medical Center in Ohio and the Oxford Centre for Haematology in the UK have discovered a link between gut health and leukemia risk due to rising amounts of ADP-heptose, a bacterial sugar, in the intestines of older individuals. The researchers published their findings in Nature.

Once circulating in the blood, ADP-heptose accelerates the expansion of DNMT3A-mutant, pre-leukemic blood cells by activating the receptor protein ALPK1.^1,2 DNMT3A-mutant hematopoietic stem cells are associated with clonal hematopoiesis of indeterminate potential (CHIP).²

Patients with myelodysplastic syndromes (MDS) had significantly higher ALPK1 mRNA levels in their hematopoietic stem cells compared with healthy control participants of the same age, which correlated with worse prognosis. Those with high ALPK1 expression also had more DNMT3A mutations.²

Therefore, the researchers identified the ADP-heptose–ALPK1 axis as a promising therapeutic target to prevent the progression of CHIP to leukemia.¹

“One of our goals is to develop an ALPK1 inhibitor that can be used in humans,” Daniel Starczynowski, PhD, director of the Advanced Leukemia Therapies and Research Center at Cincinnati Children’s Hospital Medical Center and senior author of the study, said in a press release.¹

The researchers performed experiments on mouse models to explore the mechanisms in which circulating ADP-heptose promotes pre-leukemic cell expansion. Mice with DNMT3A-deficient hematopoietic cells received dextran sulfate sodium that damaged the intestinal epithelial barrier, mimicking ulcerative colitis in humans. This process induced “significant expansion” of DNMT3A-mutant hematopoietic cells, and expansion was not observed in young mice.²

However, ADP-heptose is also found in individuals of all ages with irritable bowel syndrome (IBD).²

Using integrated flow cytometry and fluorescence microscopy, Dr. Starczynowski and colleagues also confirmed that circulating ADP-heptose in the plasma of older individuals and those with CHIP and MDS rapidly induced TIFAsome formation in leukemia cells.

Plasma from young healthy individuals did not induce TIFAsomes, but plasma from young individuals with IBD did induce TIFAsomes.²

“This study significantly advances our understanding about how blood cancers develop and progress, especially in older adults,” Dr. Starczynowski said in a press release.¹ “The exciting news is that we also may have a way to intervene early—before these pre-leukemic cells evolve into more aggressive disease.”

References

1. PR Newswire. Accessed May 16, 2025. https://www.prnewswire.com/news-releases/bacteria-in-our-aging-guts-can-elevate-risk-of-leukemia-302436300.html
2. Agarwal P, et al. Nature. 2025. https://www.nature.com/articles/s41586-025-08938-8