PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression

Abstract Internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase-3 (FLT3) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with poor prognosis. FLT3-ITD mutations result in endoplasmic reticulum (ER) retention and constitutive autophosphorylation of FLT3. The PR/SET domain 16 (PRDM16) is highly expressed in patients with FLT3-ITD+ AML, suggesting it might play a role in leukemogenesis. Here, we revealed that genetic and pharmacologic suppression of PRDM16 greatly slowed the progression of FLT3-ITD–driven leukemia, sensitized leukemic cells to tyrosine kinase inhibitors, and extended the survival of leukemic mice. PRDM16 enhanced activation of oncogenic FLT3-ITD and ligand-dependent activation of wild-type FLT3 in leukemic cells. Mechanistically, PRDM16 mediated monomethylation of FLT3-ITD at lysine-614 and promoted its ER localization, resulting in enhanced FLT3 signaling in leukemia cells. Moreover, pharmacologic suppression of FLT3-ITD methylation in combination with tyrosine kinase inhibitors increased the elimination of FLT3-ITD+ AML cells. Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML. Significance: Monomethylation of FLT3-ITD at lysine-614 by PRDM16 induces FLT3 ER localization and enhanced signaling, which can be inhibited by targeting PRDM16 to suppress survival of FLT3-ITD+ AML cells and increase chemosensitivity.