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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Leukocyte, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Sebastian Koschade

LAB HEAD: Christian Münch

PROVIDER: PXD034080 | Pride | 2022-08-25

REPOSITORIES: Pride

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Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia.

Koschade Sebastian E SE Klann Kevin K Shaid Shabnam S Vick Binje B Stratmann Jan A JA Thölken Marlyn M Meyer Laura M LM Nguyen The Duy TD Campe Julia J Moser Laura M LM Hock Susanna S Baker Fatima F Meyer Christian T CT Wempe Frank F Serve Hubert H Ullrich Evelyn E Jeremias Irmela I Münch Christian C Brandts Christian H CH

Leukemia 20220823 10

Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25 % of acute myeloid leukemia (AML) patients, drive leukemia progression and confer a poor prognosis. Primary resistance to FLT3 kinase inhibitors (FLT3i) quizartinib, crenolanib and gilteritinib is a frequent clinical challenge and occurs in the absence of identifiable genetic causes. This suggests that adaptive cellular mechanisms mediate primary resistance to on-target FLT3i therapy. Here, we systematically inve ...[more]

PMID: 35999260

Similar Datasets

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

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

DNR pulse treatment of primary AML

Project description:Primary human AML bone marrow sample (newly diagnosed, prior to treatment initation) was obtained from donor after consent and AML blasts were isolated by standard Ficoll centrifugation. AML blasts were pulse-treated with daunorubicine (100 nM, 200 nM, 400 nM) or DMSO control for 1 hour, followed by wash-out and short-term cell culture to allow cellular responses to develop. 20,000 cells were analysed by LC-MS3, and 5,000 cells were subjected to flow cytometry apoptosis assay.

2022-10-15 | PXD030280 | Pride

PAM complex sequesters from TIM translocon and becomes part of an insoluble protein fraction under protein folding stress

Project description:Upon mitochondrial dysfunction, mitophagy has been described to be activated by a breakdown of membrane potential leading to PINK1 accumulation on the outer membrane and engulfment of mitochondria for degradation. However, recent findings have indicated that mitophagy may also be triggered in the absence of membrane potential alterations. Here, we report mechanistic details on how inhibition of protein import induces mitophagy independent of mitochondrial membrane depolarization. Carrying out a genome-wide CRISPR/Cas9 screen for regulators of mitophagy, we found that the pre-sequence translocase-associated motor complex PAM controls mitophagy induction. Loss of PAM caused defects in protein import and was sufficient to induce mitophagy without depolarization. Quantitative interaction and aggregation proteomics revealed that PAM was highly sensitive to proteostasis perturbation; upon misfolding conditions, PAM dissociated from the import machinery, sequestered into the insoluble fraction and caused mitophagy despite an intact membrane potential. Our findings extend the current mitophagy model and provide mechanistic insight into how proteostasis perturbation leads to mitophagy induction. They reveal the PAM complex as key folding sensor integrating proteostasis, import and mitophagy.

2022-09-03 | PXD022524 | Pride

PAM complex sequesters from TIM translocon and becomes part of an insoluble protein fraction under protein folding stress

2022-09-03 | PXD022530 | Pride

Functional translatome proteomics reveal converging regulation by mTORC1 and eIF2α

Project description:Regulation of the translatome is essential during stress. However, the precise sets of translational targets regulated by the key translational stress responses –integrated stress response (ISR) and mTORC1 – remain elusive. We developed multiplexed enhanced protein dynamics (mePROD) proteomics, combining dynamic SILAC, multiplexing, and signal amplification, to enable measuring acute changes in protein synthesis. Treating cells with ISR/mTORC1-modulating stressors, we showed extensive translatome modulation and ~20% of proteins synthesized at highly reduced rates. Comparing translation-deficient sub-proteomes revealed an extensive overlap demonstrating that target specificity is achieved on protein level and not by pathway activation. Titrating inhibition of cap-dependent translation confirmed that synthesis of individual proteins is controlled by intrinsic properties responsive to global translation inhibition. This study reports a method to measure translation rates at the nascent chain level and provides insight into how the ISR and mTORC1, two key cellular pathways, regulate the translatome to guide cellular survival upon stress.

2019-12-06 | PXD014377 | Pride

Functional Translatome Proteomics Reveal Converging and Dose-Dependent Regulation by mTORC1 and eIF2α

2019-12-09 | PXD015438 | Pride

Protein import defects induce mitophagy without membrane depolarization

2022-09-03 | PXD022560 | Pride

Endogenous anti-tumorigenic nitro-fatty acids potently suppress the ubiquitin-proteasome system

Project description:Nitro-fatty acids (NFAs) are endogenously formed lipid mediators that cause a broad spectrum of anti-inflammatory effects by covalent modification of key proteins within inflammatory signaling pathways. Their potential as therapeutics has been demonstrated in numerous animal models of disease. Herein, we evaluated the anti-tumorigenic effects of NFAs in the colon carcinoma cell line Caco-2 and other solid and leukemic tumor cell lines. NFAs inhibited the ubiquitin–proteasome system (UPS), leading to polyubiquitination and inhibition of the proteasome activities. Suppression of the UPS induced the pro-apoptotic transcription factor CHOP by activation of the unfolded protein response (UPR), resulting in tumor cell death. NFA-mediated effects on UPS and UPR were rather strong, highly specific, largely irreversible, and represent a mechanistically new mode of action for pharmacological suppression of the UPS. Taking into account their favorable safety profile in clinical phase I trials in combination with their well-recognized anti-tumorigenic efficacy covering solid tumors, we conclude that NFAs are innovative proteasome inhibitor drug candidates that may have a large potential to overcome the limitations of the classical proteasome inhibitors.

2024-03-26 | PXD023372 | Pride

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