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Glucocorticoids enhance the anti-leukemic activity of FLT3 inhibitors in FLT3 mutant acute myeloid leukemia

ABSTRACT: Glucocorticoids enhance the anti-leukemic activity of FLT3 inhibitors in FLT3 mutant acute myeloid leukemia

PROVIDER: PRJNA478462 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11868229_1.fastq.gz	Fastqsanger.gz
	SRR11868229_2.fastq.gz	Fastqsanger.gz
	SRR11868230_1.fastq.gz	Fastqsanger.gz
	SRR11868230_2.fastq.gz	Fastqsanger.gz
	SRR11868231_1.fastq.gz	Fastqsanger.gz

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Glucocorticoids enhance the anti-leukemic activity of FLT3 inhibitors in FLT3 mutant acute myeloid leukemia

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

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Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia.

Project description:FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor-dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.

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Project description:The interaction of Menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and potential therapeutic opportunity against NPM1 mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. Transcriptional profiling upon pharmacological inhibition of the Menin-MLL complex revealed specific changes in gene expression with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being most pronounced. Combining Menin-MLL inhibition with specific small molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream to FLT3 signaling. The drug combination induced synergistic inhibition of proliferation as well as enhanced apoptosis and differentiation compared to single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary AML cells harvested from patients with NPM1mut FLT3mut AML showed significantly better responses to combined Menin and FLT3 inhibition than to single-drug or vehicle control treatment, while AML cells with wildtype NPM1, MLL, and FLT3 were not affected by any of the two drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared to the single-drug and vehicle control groups. Our data suggest that combined Menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.

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