Our experimental studies in mice corroborate the observations in the patient cohort, providing a proof of concept that obesity-induced changes can promote the expansion of pre-leukemic CHIP to a severe MPN-like phenotype in mouse models using several CHIP-associated genes including Tet2, Dnmt3a, Asxl1, and Jak2. This evidence concerns the gene DNMT3A and obesity due to melanocortin 4 receptor deficiency.