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Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia

ABSTRACT: Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-RES-Luc+ (MOLM13 cells with a D835Y mutation generating a resistant phenotype) AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitor (gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 13 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and ATAC-seq was performed on HiSeq 4000, total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the chromatin accessibility changes induced by gilteritinib in MOLM13-RES AML xenograft model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179421 | GEO | 2021/07/07

REPOSITORIES: GEO

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Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia (RNA-Seq I)

Project description:Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-RES-Luc+ (MOLM13 cells with a D835Y mutation generating a resistant phenotype) AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitors (TP-0903, 60 mg/kg, once daily for 5 days/week; gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 13 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and RNA-seq was performed on total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the transcriptional changes induced by TP-0903 or gilteritinib in MOLM13-RES AML xenograft model.

2021-07-22 | GSE180180 | GEO

Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in Acute Myeloid Leukemia (RNA-Seq II)

Project description:Purpose: Compare transcriptional changes between drug treated (gilteritinib, TP-0903) and vehicle in acute myeloid leukemia xenografts. Methods: FLT3-ITD+ MOLM13-Luc+ AML cells were xenografted into NSG mice. Mice were randomized according to bioluminescence imaging, and treatment of FLT3 tyrosine kinase inhibitors (TP-0903, 60 mg/kg, once daily for 5 days/week; gilteritinib, 30 mg/kg, once daily for 5 days/week) was started on day 7 post-tail vein injection. At study end point, mice were humanely euthanized and bone marrow was collected. AML cells (human CD45+) were isolated, and RNA-seq was performed on total RNA. Sequencing reads were aligned and analyzed for differential gene expression of treatment vs vehicle cohorts. Results: The analysis revealed the transcriptional changes induced by TP-0903 or gilteritinib in MOLM13 AML xenograft model.

2021-07-22 | GSE180181 | GEO

Phosphoproteomics of primary human FLT3-ITD+ AML cells treated with gilteritinib

Project description:Primary human AML cells (newly diagnosed, prior to treatment initation) were obtained from donor after consent and AML blasts were isolated by standard Ficoll centrifugation. AML blasts were treated with FLT3 inhibitor gilteritinib (or DMSO vehicle control) at 10 nM concentration for 6 h, followed by harvest for LC/MS.

2022-08-25 | PXD034080 | Pride

Assessment of chromatin remodeling of acute myeloid leukemia cells treated with gilteritinib

Project description:Gilteritinib is a FLT3 inhibitor that has been approved for relapsed acute myeloid leukemia (AML) carrying FLT3 mutations. However, the effects of this drug on chromatin remodeling of AML cells remains unknown. We tested the state of chromatin openness of AML cells obtained from a patient before and after treatment with gilteritinib using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq).

2022-08-09 | GSE210617 | GEO

Translatome proteomics of primary human FLT3-ITD+ AML cells treated with FLT3 inhibitors quizartinib, crenolanib, gilteritinib

Project description:Primary human AML cells (newly diagnosed, prior to treatment initation) was obtained from donor after consent and AML blasts were isolated by standard Ficoll centrifugation. Cells were treated ex vivo with DMSO vehicle control or 10 nM FLT3 inhibitors quizartinib, crenolanib, gilteritinib for 6 hours in SILAC medium and processed for LC/MS.

2022-08-25 | PXD034081 | Pride

BMX Kinase Mediates Gilteritinib Resistance in FLT3-mutated AML through Microenvironmental Factors

Project description:While clinical benefit has been observed with gilteritinib, most patients relapse through unknown mechanisms. To investigate mechanisms of gilteritinib resistance, we performed targeted genomic sequencing and single cell (sc) RNASeq on primary FLT3-ITD-mutated AML samples. Co-occurring mutations in RAS pathway genes were the most common. In gilteritinib-unresponsive patients, increased expression of bone marrow-derived hematopoietic cytokines and chemokines was observed after treatment compared to gilteritinib-sensitive patients. Expression of the TEK-family kinase, BMX, was higher in gilteritinib-unresponsive patients after treatment compared to gilteritinib-sensitive patients. BMX contributed to gilteritinib resistance in FLT3-mutant cells lines in a hypoxia-dependent manner by promoting pSTAT5 signaling, which was reversed with pharmacological inhibition and genetic knockout. In primary FLT3-mutated AML samples, pharmacological inhibition of BMX enhanced the antileukemic activity of gilteritinib and decreased chemokine expression. Gene module analysis associated gilteritinib responsiveness with lymphocyte differentiation and myeloid leukocyte activation. By contrast, unresponsiveness to gilteritinib associated with upregulation of cell-cycle, DNA/RNA metabolic processes, and protein translation. Together, these data support a role for microenvironment-mediated factors modulated by BMX in the escape from targeted therapy and gilteritinib resistance. This analysis provides a deeper understanding of targets and pathways for potential therapeutic intervention to restore gilteritinib sensitivity.

2022-07-07 | GSE199333 | GEO

shCDK9 or shDHODH sensitizes cells to gilteritinib treatment by altering transcriptomes of AML cells

Project description:Acquisition of an internal tandem duplication of the juxtamembrane region of FLT3 (FLT3-ITD) is a common event in Acute myeloid leukemia (AML) patients and is associated with poor outcomes at high allelic frequency. Although targeted therapies against FLT3-ITD exist, narrow therapeutic index as monotherapies and failure to achieve complete remission limits their clinical application. Using a genome-wide CRISPR knockout screen, we identified cyclin-dependent kinase (CDK9), protein arginine methyltransferase (PRMT5) and dihydroorotate dehydrogenase (DHODH) as novel synthetic lethal partners with gilteritinib treatment. We demonstrated that genetic or pharmacologic inhibition of these targets in combination with gilteritinib synergistically kill AML cells. The presence of FLT3-ITD was shown to cause a significant increase in aerobic glycolysis, rending the leukemia cells highly sensitive to pharmacological inhibition of glycolytic activity. Supportive of this, our screen shows that sgRNAs targeting ~28 genes in the glycolysis pathway are enriched in cells treated with gilteritinib, suggesting that switching to oxidative phosphorylation from aerobic glycolysis may represent a metabolic adaption of the leukemic cells to resistance to FLT3-targeted therapy. Interestingly, the knockdown of CDK9, PRMT5 or DHODH in presence of gilteritinib cooperatively shuts down oxidative phosphorylation and associated purine biosynthesis and mevalonate pathway, implying inhibition of these genes along with proteins involved in the mitochondria respiratory chain complexes and energy metabolism may represent an attractive strategy to resensitize leukemic cells to gilteritinib treatment. Overall, these findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and provide a rationale for a clinical trial of these novel combinatorial therapies.

2022-09-21 | GSE185519 | GEO

Phosphoproteomics of human MV4-11 AML cells treated with Gilteritinib

Project description:Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25% of acute myeloid leukemia (AML) patients and lead to constitutive activation of FLT3, driving leukemia cell survival and proliferation. Quizartinib, crenolanib and gilteritinib are second-generation FLT3 inhibitors (FLT3i) in phase III trials or clinical use for the targeted treatment of FLT3-ITD+ AML. However, they demonstrated only limited benefit and were not curative. A full understanding of cellular resistance factors contributing to this poor response is lacking. Here, we examined cell-autonomous pathways modulated by FLT3i using global translatome and phosphoproteome proteomics to identify non-genetic resistance mechanisms.

2022-08-25 | PXD023123 | Pride

Translatome proteomics of human AML cells treated with FLT3 inhibitors quizartinib, crenolanib, gilteritinib

2022-08-25 | PXD023125 | Pride

Transcriptomic effects of combination Menin-MLL1 inhibition and FLT3 inhibition on human AML cells

Project description:Chromosomal translocations of the MLL1 gene cooccur with the activating mutations in FLT3 kinase in acute myeloid leukemia patients, providing the rationale to explore combination of the menin-MLL1 inhibitor (MI-3454) and FLT3 inhibitor (Gilteritinib) in leukemia models. Here, we pursued global gene expression studies after 7 days of treatment of MOLM13 cells (harboring MLL-AF9 and FLT3-ITD) with MI-3454 and Gilteritinib used as single agents and in combination. We observed that MYC, differentiation and stemness-associated gene programs were disrupted by the single agent treatments, but the effect was enhanced upon combinatorial treatment. These results provide a mechanistic input on the increased activity of MI-3454 when combined with Gilteritinib in leukemia models versus single agent treatment.

2020-12-17 | GSE149049 | GEO

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