Mutation-Specific Differences in the Relationship between Obesity and Clonal Hematopoiesis, with a Focus on JAK2V617F and MPN Prevention

• Published in: Blood 2024-11, Vol.144, p.872-872
• Main Authors: Rolles, Benjamin, Sekar, Aswin, Serrano-Ron, Laura, Ameerul Faiz, Noorul Mifra, Perry, Andrea, Hillerbrandt, Addison Clare, Hem, Jessica, Jutzi, Jonas, Marneth, Anna E., Niroula, Abhishek, Bick, Alexander G., Gibson, Christopher J., Griffin, Gabriel K., Uddin, Md Mesbah, Natarajan, Pradeep, Ebert, Benjamin Levine, van Galen, Peter, Al-Shahrour, Fatima, Hormoz, Sahand, Mullally, Ann
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-204211

Introduction: Although the inferred “fitness” of clonal hematopoesis (CH) driver mutations differs depending on the gene mutation, the impact of environmental factors that may promote or impair CH expansion remain largely unknown. We hypothesized that obesity influences the clonal expansion rate of common CH driver mutations. Methods: To test this hypothesis, we first interrogated data from the UKBiobank (UKBB) (n=425,573 exomes) to evaluate the relationship between body mass index (BMI) (kg/m2) and four common CH mutations, namely DNMT3A, TET2, ASXL1, and JAK2. For functional studies we focused on JAK2V617F, using a novel Fgd5-CreER-Jak2V617F mouse model we generated. In this model, Jak2V617F expression is induced in a small percentage of long-term (LT)-HSC which are tracked sequentially in primary mice in an unirradiated bone marrow niche. To quantify Jak2V617F expression in the model, we developed a digital droplet PCR assay. We also generated a chimeric bone marrow transplant Jak2V617F model and performed bulk RNA-sequencing (RNAseq) on purified lineagelow Sca-1+ c-kithigh (LSK) cells expressing Jak2V617F or wild-type Jak2, isolated from the same mouse. Finally, we performed single-cell RNAseq on Jak2V617F-expressing c-kithigh cells purified from chimeric transplant mice. Mice fed an obesity diet received 60 kcal% fat while mice fed a control diet received 10 kcal% fat. Results: In UKBB analyses, we identified genotype-specific patterns of association between BMI and the presence of CH mutations. JAK2 (OR 0.51; 95% CI 0.27-0.96; p=0.036) and DNMT3A mutations (OR 0.92; 95% CI 0.87-0.97; p=0.0028) were negatively associated with a BMI >30 relative to BMI 30. To further explore the negative association between JAK2V617F and obesity, we generated a cohort of Fgd5-CreER-Jak2V617F mice and fed half the mice an obesity diet and the other half a control diet. After 24 weeks, Jak2-mutant mice fed the control diet developed a significantly higher hematocrit (HCT) as compared to Jak2-mutant mice fed the obesity diet (p=0.0043). The HCT remained significantly higher in control mice as compared to obese mice over a 46-week period (p