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Targeting CERT sensitizes AML Cells to FLT3 Inhibitors through activating GRP78-ATF6-CHOP Axis

ABSTRACT: Ceramide Transfer Protein (CERT) determines the ratio of ceramide and Sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, the role of CERT in AML remains elusive. Knockdown CERT or its inhibitor HPA-12 inhibited growth and promoted apoptosis in AML cells carrying FLT3-ITD mutation. HPA-12 alone or with the FLT3 inhibitor Crenolanib synergistically inhibited proliferation and triggered apoptosis in FLT3-ITD mutated AML cells in vitro and in vivo. Interestingly, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects were mediated by the endoplasmic reticulum (ER) stress-GRP78/ATF6/CHOP axis and mitophagy. Our data suggest a possible strategy to enhance the efficacy of FLT3 inhibitors in AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280391 | GEO | 2024/12/01

REPOSITORIES: GEO

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Crenolanib in combination with azacitidine abrogates stromal protection and survival of leukemia-initiating cells in FLT3-ITD+ AML

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Clinical Crenolanib Resistance in AML

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| phs001628 | dbGaP

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Project description:The purpose of the experiment is to investigate transcriptome signatures of FLT3-ITD and TKD double mutations in AML and the underlying molecular mechanism of mutation-driven acquired resistance. We identify that 310 upregulated and 22 downregulated promoters in FLT3-ITD/D835 mutant AML cells compared to cells with FLT3-ITD (FDR<0.05).

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Cap analysis gene analysis (CAGE) of Ba/F3 cells harbouring FLT3-ITD mutations (mouse)

Project description:The purpose of the experiment is to investigate transcriptome signatures of FLT3-ITD and TKD double mutations in AML and the underlying molecular mechanism of mutation-driven acquired resistance. We identify 1945 upregulated and 1470 downregulated promoters in FLT3-ITD/D835 mutant Ba/F4 cells compared to cells with FLT3-ITD (FDR<0.05).

2023-05-08 | GSE149963 | GEO

Cap analysis gene analysis (CAGE) of AML cells harbouring FLT3-ITD mutations

Project description:This SuperSeries is composed of the SubSeries listed below. The purpose of the experiment is to investigate transcriptome signatures of FLT3-ITD and TKD double mutations in AML cells (primary samples and Ba/F3 cell) and the underlying molecular mechanism of mutation-driven acquired resistance. We identify 310 upregulated and 22 downregulated promoters in FLT3-ITD/D835 mutant AML cells compared to cells with FLT3-ITD (FDR<0.05), and 1945 upregulated and 1470 downregulated promoters in FLT3-ITD/D835 mutant Ba/F3 cells compared to cells with FLT3-ITD.

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2022-08-25 | PXD023123 | Pride

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