In this study, we generated transgenic zebrafish models and demonstrated that transgenic expression of IDH2R172K and IDH2R140Q in hematopoietic stem/progenitor cells induced myeloid skewing and differentiation blockade at HSPC-MPP levels, resulting in expansion of KM, splenomegaly, myelodysplasia and increase in Mpo+ blasts capable of self-renewal in serial transplantations. The gene discussed is MPO; the disease is Splenomegaly.