Obesity-Induced Inflammation Co-Operates with Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutants to Promote Leukemia Development and Cardiovascular Disease

▪ Obesity is an increasing epidemic world-wide responsible for enhancing the risk for developing Type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) and cancer. However, it is unclear if and how obesity contributes to the transformation of pre-leukemic stem and progenitors (pre-LHSC/Ps) into full-blown leukemia such as acute myeloid leukemia (AML) or severe form of myeloproliferative neoplasm (MPN) or CVD. We hypothesized that obesity induced chronic inflammation might be responsible for clonal selection of pre-LHSC/Ps bearing pre-leukemic clonal hematopoiesis of indeterminate potential (CHIP) mutations such as DNMT3A, TET2, ASXL1, and JAK2 and for promoting the progression of early-onset MPN, AML/leukemia and CVD. To study the linkage between obesity and CHIP in humans, we first examined the UK biobank. After exclusions, the final study cohort included 47,466 unrelated participants free of T2DM at baseline and having valid CHIP measurements. The mean (SD) age at enrollment was 56.5 (8.0), 45.0% were male, 43.9% never smoked, and 82.6% self-reported as European decedents. At baseline, the mean (SD) body mass index (BMI) was 27.3 (4.7) kg/m 2, with 43.0% overweight and 23.6% obese, and the overall mean (SD) waist-to-hip ratio (WHR) was 0.87 (0.09). CHIP was present among 5.8% of the study population the most common mutations on the DNMT3A (3.7%) and TET2 (1.0%) genes; large CHIP clone defined as CHIP mutation with variant allele fraction >10% was present among 2.4% of the study population. Individuals with CHIP mutations on average had higher WHR. The presence of CHIP mutation was associated with a 0.0028 increase of WHR (p=0.03). Furthermore, CHIP prevalence increased with higher WHR: the percentage of participants with CHIP was 4.93%, 5.75%, 6.56% in the lowest, middle, and highest WHR quintiles respectively, signifying that dysfunctional metabolism may accelerate expansion of clonal hematopoiesis (CH). To better define the mechanism of obesity driven CH, we utilized several novel mouse models bearing Tet2 -/-, Dnmt3a +/-, Asxl1 +/- and Jak2 +/- mutations to mimic the human pre-LHSC/Ps condition and obesity, in the form of leptin deficient Lep Ob/Ob (Ob/Ob) mutation, which induces obesity and T2DM. We show that both the compound mutant (Tet2 -/-;Ob/Ob, Dnmt3a +/-;Ob/Ob, Asxl1 +/-;Ob/Ob and Jak2 +/-;Ob/Ob) and CHIP mutant bone marrow (BM; Tet2 -/-, Dnmt3a +/-, Asxl1 +/- and Jak2 +/-) transplanted into Ob/Ob mice develop rapid growth of mature mye