Key Points

  • FLT3-ITD is S-palmitoylated at cysteine 563 by the acyltransferase ZDHHC6.

  • Disruption of FLT3-ITD palmitoylation changes FLT3-ITD localization, rewires its downstream signaling, and promotes leukemic progression.

Internal tandem duplication within FLT3 (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and correlates with poor prognosis. While FLT3 receptor tyrosine kinase is activated at the plasma membrane to transduce PI3K/AKT and RAS/MAPK signaling, FLT3-ITD resides in the endoplasmic reticulum (ER) and triggers constitutive STAT5 phosphorylation. Mechanisms underlying this aberrant FLT3-ITD subcellular localization or its impact on leukemogenesis remain poorly established. Here we discover that FLT3-ITD is S-palmitoylated by the ZDHHC6 palmitoyl acyltransferase. Disruption of palmitoylation redirected FLT3-ITD to the plasma membrane and rewired its downstream signaling by activating AKT and ERK pathways in addition to STAT5. Consequently, abrogation of palmitoylation increased FLT3-ITD-mediated leukemic progression in xenotransplanted mouse models. We further demonstrate that FLT3 proteins were palmitoylated in primary human AML cells. ZDHHC6-mediated palmitoylation restrained FLT3-ITD surface expression, signaling and colonogenic growth of primary FLT3-ITD+ AMLs. More importantly, pharmacological inhibition of FLT3-ITD depalmitoylation synergized with FDA-approved FLT3 kinase inhibitor gilteritinib in abrogating the growth of primary FLT3-ITD+ AML cells. These findings provide novel insights into lipid-dependent compartmentalization of FLT3-ITD signaling in AML and suggest targeting depalmitoylation as a new therapeutic strategy to treat FLT3-ITD+ leukemias.

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