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PXD010193

PXD010193 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleBCL2 amplicon loss and super-enhancer remodeling drives ABT-199 resistance
DescriptionDrug-tolerant “persister” tumor cells underlie the emergence of drug-resistant clones contribute to relapse and disease progression; thus, identifying actionable targets that disable persisters and mitigate relapse are a high priority need. Although the BCL2-targeting agent venetoclax (ABT-199) has shown promising responses in mantle cell and double hit B cell lymphomas, resistance often arises, yet mechanistically how this occurs is unclear. Here we report that ABT-199 resistance can evolve from persister clones that have selective deletions at 18q21 that involve the drug target BCL2 and the apoptotic regulators Noxa (PMAIP1) and TCF4. Notably, reprogramming of super enhancers (SE) in persisters contributes to resistance, where there is a selection for SE-directed overexpression of the apoptotic regulator BCL2A1 and oncogenic transcription factors IKZF1 and FOXC1. At the same time, the SE reprogramming confers an opportunity for overcoming ABT-199 resistance. An unbiased drug screen on a platform that recapitulates the lymphoma microenvironment revealed that persisters are vulnerable to inhibitors of transcription initiation and elongation, and especially so to inhibitors of cyclin-dependent kinase 7 (CDK7) that is essential for transcription initiation. Specifically, CDK7 loss or inhibition eliminated the persister phenotype by disabling SE-driven expression of BCL2A1, IKZF1 and FOXC1. Thus, the co-treatment of ABT-199 with CDK7 inhibitors blocked the evolution of drug resistance, and provoked tumor regression in models of mantle cell lymphoma (MCL) and double hit lymphomas (DHL) that overexpress both MYC and BCL2. Together, these findings establish loss of apoptotic regulators and an adaptive transcriptional response as drug resistance mechanisms in lymphoma, more importantly, establish a rationale for transcription inhibition-based combination strategies to prevent and overcome drug resistance in B cell malignancies toward BCL2 inhibitor.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:04:49.186.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD010193
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterJohn Koomen
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListBiotin:Thermo-88310; Oxidation; Carbamidomethyl
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-06-22 02:50:48ID requested
12020-05-26 11:56:29announced
22024-10-22 05:04:57announced2024-10-22: Updated project metadata.
Publication List
10.6019/PXD010193;
Zhao X, Ren Y, Lawlor M, Shah BD, Park PMC, Lwin T, Wang X, Liu K, Wang M, Gao J, Li T, Xu M, Silva AS, Lee K, Zhang T, Koomen JM, Jiang H, Sudalagunta PR, Meads MB, Cheng F, Bi C, Fu K, Fan H, Dalton WS, Moscinski LC, Shain KH, Sotomayor EM, Wang GG, Gray NS, Cleveland JL, Qi J, Tao J, BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models. Cancer Cell, 35(5):752-766.e9(2019) [pubmed]
10.1016/j.ccell.2019.04.005;
Keyword List
curator keyword: Biomedical
submitter keyword: ABPP, lymphoma, persister,apoptosis
Contact List
Jianguo Tao MD/PhD
contact affiliationMoffitt Cancer Center
contact emailjianguo.tao@moffitt.org
lab head
John Koomen
contact affiliationMoffitt Cancer Center
contact emailjohn.koomen@moffitt.org
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
Repository Record List
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