Smyd3 KO CML mice RNA seq

The development of BCR-ABL tyrosine kinase inhibitors (TKIs) has revolutionized disease management of chronic myeloid leukemia (CML). However, the persistence of leukemia stem cells (LSCs) remains a big barrier to cure. There is an urgent need to identify the regulators uniquely driving LSCs. In this study, we validated the critical role of SET and MYND domain containing 3 (SMYD3) in the maintenance of LSCs in CML. SMYD3 was overexpressed in CML LSCs and enhanced the survival and self-renewal properties of human primary CML CD34+ cells. Loss of Smyd3 greatly blocked leukemogenesis and impaired the self-renewal and disease reconstitution abilities of LSCs in CML mice without affecting normal hematopoiesis. SMYD3 regulated LSCs in a methyltransferase activity-dependent manner.

BCR-ABL酪氨酸激酶抑制剂（BCR-ABL tyrosine kinase inhibitors, TKIs）的开发彻底革新了慢性髓性白血病（chronic myeloid leukemia, CML）的疾病管理。然而，白血病干细胞（leukemia stem cells, LSCs）的存续仍是治愈该疾病的核心障碍，当前亟需鉴定出特异性驱动LSCs的调控因子。本研究验证了SET和MYND结构域包含蛋白3（SET and MYND domain containing 3, SMYD3）在维持CML中LSCs的关键作用。SMYD3在CML LSCs中呈过表达状态，可增强人原代CML CD34+细胞的存活能力与自我更新特性。Smyd3缺失可显著阻断CML小鼠的白血病发生过程，并损害LSCs的自我更新及疾病重建能力，且不会对正常造血功能造成影响。SMYD3通过依赖其甲基转移酶活性的方式调控LSCs。