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The development of BCR-ABL tyrosine kinase inhibitors has revolutionized disease management of chronic myeloid leukemia (CML). However, the persistence of leukemia stem cells (LSC) remains a major barrier to curing CML, highlighting the urgent need to identify the regulators supporting LSCs. In this study, we validated the critical role of the histone methyltransferase 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 blocked leukemogenesis and impaired the self-renewal and disease reconstitution abilities of LSCs in mice without affecting normal hematopoiesis. SMYD3 stimulated fatty acid β-oxidation (FAO) in LSCs by activating the FABP5/PPARD/CPT1A signaling axis in a methyltransferase activity-dependent manner. Blocking CPT1A-mediated FAO reduced the function of human CML LSCs in vitro and depleted LSCs in vivo. These findings shed light on the role of histone lysine methylation-mediated FAO in the maintenance of LSCs and suggest that SMYD3 may serve as a therapeutic target for treating patients with CML. Significance: The epigenetic modulator SMYD3 promotes leukemogenesis and self-renewal of leukemia stem cells by upregulating FABP5 to stimulate fatty acid β-oxidation, which can be targeted to treat chronic myeloid leukemia.
Zhou et al. (Thu,) studied this question.