PXD047149

PXD047149 is an original dataset announced via ProteomeXchange.

Title	BCL-2 Regulation and Upstream Signal Transduction Modulate Venetoclax Resistance in Multiple Myeloma: New Avenues for Therapeutic Intervention
Description	This study aimed to investigate the mechanisms underlying venetoclax (VTX) resistance in multiple myeloma (MM) and develop strategies to prevent or overcome resistance. VTX resistant human myeloma cell lines (HMCLs) were established and analyzed using whole exome sequencing (WES), mRNA-sequencing (mRNAseq), and protein expression assays, along with samples from MM patients collected before and after VTX administration. Acquired VTX-resistance in MM was largely associated with BCL-2 family regulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2 and downregulation of pro-apoptotic members. No BCL-2 mutation was detected in resistant cell lines or relapse patient samples. We also identified upstream signaling pathways involved in BCL-2 family regulation during acquired resistance, such as cytokine, growth factor receptor tyrosine kinase (RTK)-activated signaling, including the PI3K pathway. MCL-1 stability was also investigated through modulation of post-translational modification, but targeting MCL-1 stability via specific inhibitors had limited success in enhancing VTX sensitivity. Co-inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Additionally, the inhibition of AURKA and mitochondrial respiration also affected VTX sensitivity in some resistant HMCLs. The findings underscore the importance of personalized approaches to overcome resistance in relapsed patients, suggesting that combining venetoclax with MCL-1 and BCL-XL inhibitors, or targeting upstream regulatory pathways, warrants further investigation to improve patient outcomes and prolong survival in MM.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_12:27:15.140.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Akhilesh Pandey
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-21 19:15:09	ID requested
⏵ 1	2025-05-06 12:27:15	announced

10.1038/s41408-025-01215-x;

Fonseca R, Zhu YX, Bruins LA, Ahmann J, de Bonolo Campos C, Braggio E, Chen X, Arribas M, Darvish S, Welsh S, Meermeier E, Mangalaparthi KK, Kandasamy RK, Ahmann G, Wiedmeier-Nutor JE, Pandey A, Chesi M, Bergsagel PL, Fonseca R, Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention. Blood Cancer J, 15(1):10(2025) [pubmed]

submitter keyword: Venetoclax, Acquired resistance, BCL-2, Proteomics,Multiple Myeloma

Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester MN
contact email	pandey.akhilesh@mayo.edu
lab head
Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905
contact email	pandey.akhilesh@mayo.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047149
     1. Label: PRIDE project
     2. Name: BCL-2 Regulation and Upstream Signal Transduction Modulate Venetoclax Resistance in Multiple Myeloma: New Avenues for Therapeutic Intervention