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Depalmitoylation rewires FLT3-ITD signaling and exacerbates leukemia progression.

ABSTRACT: Internal tandem duplication within FLT3 (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and correlates with a poor prognosis. Whereas the 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 and triggers constitutive STAT5 phosphorylation. Mechanisms underlying this aberrant FLT3-ITD subcellular localization or its impact on leukemogenesis remain poorly established. In this study, we discovered that FLT3-ITD is S-palmitoylated by the palmitoyl acyltransferase ZDHHC6. Disruption of palmitoylation redirected FLT3-ITD to the plasma membrane and rewired its downstream signaling by activating AKT and extracellular signal-regulated kinase pathways in addition to STAT5. Consequently, abrogation of palmitoylation increased FLT3-ITD-mediated progression of leukemia in xenotransplant-recipient 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+ AML. More important, pharmacological inhibition of FLT3-ITD depalmitoylation synergized with the US Food and Drug Administration-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.

SUBMITTER: Lv K

PROVIDER: S-EPMC8832469 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.

Project description:The adverse prognosis of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3-ITD) in patients with acute myelogenous leukemia (AML) may depend on allelic burden. We compared postremission treatment with chemotherapy and hematopoietic stem cell transplantation (HSCT) in 169 FLT3-ITDmut intermediate cytogenetic risk AML patients with allelic ratio evaluable at diagnosis who achieved first complete remission (CR1) with induction therapy. To minimize selection bias, the analysis was limited to patients who remained in CR1 for at least 4 months (median time to HSCT) after achieving CR1, and propensity score matching was implemented. Sensitivity analysis including patients who remained in CR1 for at least 3 months was applied as well. HSCT in CR1 was associated with longer relapse-free survival (RFS) and overall survival (OS), with 3-year estimated rates of 18% and 24%, respectively (P < .001), for patients receiving chemotherapy and 46% and 54%, respectively (P < .001), for those undergoing HSCT. Multivariate regression models showed that HSCT remained statistically significant with improved RFS and OS independent of FLT3-ITD allelic ratio and NPM1 status. Irrespective of postremission therapy, relapse remains the main reason for treatment failure, with a 3-year incidence of 68% in chemotherapy recipients versus 41% in HSCT recipients. Allogeneic HSCT improved disease outcomes compared with chemotherapy after propensity score matching was applied. The improvement observed for RFS (hazard ratio [HR], 0.55; P = .09) and OS (HR, 0.58; P = .10) with HSCT as postremission therapy in patients who remained in CR1 for at least 4 months did not reach statistical significance; however, the sensitivity analyses including patients who remained in CR1 for at least 3 months showed significant improvement in both RFS (HR, 0.31; P = .002) and OS (HR, 0.27; P = .02) after propensity score matching. Our results indicate that HSCT in CR1 for AML FLT3-ITDmut patients is associated with longer RFS and OS. Innovative transplantation strategies to improve relapse incidence are urgently needed.

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Depalmitoylation rewires FLT3-ITD signaling and exacerbates leukemia progression.

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