We show that transgenic compound mutant mice or Ob/Ob mice transplanted with BM containing CHIP-associated mutations (Tet2–/–, Tet2+/–, Dnmt3a+/–, Asxl1+/–, and Jak2V617F/+) developed rapid CH and a severe MPN-like phenotype, which was associated with increased expression of intracellular Ca2+/Irg1/Nfatc3 signaling in Tet2-mutant cells. The gene discussed is DNMT3A; the disease is myeloproliferative neoplasm.