To mimic the common human ASXL1 mutation, p.E635RfsX15, conditional C-terminal truncated Asxl1 mutant knock-in (Asxl1-MT KI) mice were generated that impaired hematopoiesis (e.g., myeloid skewing, age-dependent mild anemia with erythroid differentiation block, modest dysplasia, and thrombocytosis) but was not sufficient to transform HSCs. Here, ASXL1 is linked to thrombocytosis disease.