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Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [DNaseI-seq]

ABSTRACT: Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [DNaseI-seq]

PROVIDER: PRJNA1009057 | ENA |

REPOSITORIES: ENA

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Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML

Project description:Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML

| PRJNA1009040 | ENA

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [DNaseI-seq]

Project description:AML is characterised by a variety of co-occurring driver mutations in genes associated with cell signallingand growth regulationsuch as the FLT3-ITD. Inhibitors targeting FLT3 (FLT3i) are beingused to treat FLT3-ITD+ patients but most relapse.By profiling the gene regulatory networks of samples from patients before and after FLT3i treatment weobservedan increase in AP-1 mediated and a loss of RUNX1 mediated connections in treatment resistant cells. Treatmentinducesupregulation of signalling pathway genesindicatingthat cytokines mediate resistance to FLT3i, with IL-3 playing a major role. IL3 rescues survival by counteracting FLT3i mediated globalRUNX1 degradation and adown-regulationof bindingof RUNX1 in chromatin.To identify inhibitors which bypass the RUNX1 barrier we inhibitedMAPK signalling with a novel pan-RAS inhibitor which overcomes cytokine mediated resistance.Our data show (I) that cytokinesinstructAML maintenance via the stabilisation of transcriptional regulators and (ii)pan-RAS drugs bypass thisbarrier, suggesting a novel approach to treatment of AML.

2024-05-01 | GSE241648 | GEO

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ChIP-seq]

Project description:Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ChIP-seq]

| PRJNA1009052 | ENA

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ATAC-seq]

Project description:Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ATAC-seq]

| PRJNA1009044 | ENA

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [RNA-seq]

Project description:Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [RNA-seq]

| PRJNA1009056 | ENA

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ChIP-seq II]

Project description:Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ChIP-seq II]

| PRJNA1078309 | ENA

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ChIP-seq]

2024-05-01 | GSE241647 | GEO

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ATAC-seq]

2024-05-01 | GSE241646 | GEO

Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [RNA-seq]

2024-05-01 | GSE241649 | GEO

FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia

Project description:Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25~30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, the overall outcome of FLT3-ITD+ AML patients remains poor, and most of them would relapse very shortly. TKIs can not eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel, effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1 and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKIs treatment. Genetic or pharmacological inhibition of HDAC8 re-activates p53, abrogates leukemia maintenance and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) with a HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation as an important mechanism to resist TKIs and promote leukemia maintenance, and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.

2020-02-13 | GSE138057 | GEO

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