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PXD024119

PXD024119 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleClonal plasma cells in AL amyloidosis are dependent on pro-survival BCL-2 family proteins and sensitive to BH3 mimetics alone and in combination with front-line therapies
DescriptionAmyloid light chain amyloidosis (AL) is an incurable protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains accumulate as amyloid fibrils in vital organs and cause multi-organ dysfunction that can be rapidly fatal. Current treatment regimens, which include proteasome inhibitors, were developed for the treatment of the more common plasma cell disease multiple myeloma and have demonstrated efficacy in AL amyloidosis. However, use of these agents is frequently limited due to multi-organ dysfunction at presentation, resulting in a median survival of 2-3 years and underscoring the need for novel therapies. By analyzing bone marrow-derived plasma cells from 44 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins that can potentially be targeted by recently-developed BH3 mimetics. In particular, we find that clonal plasma cells are highly dependent on the pro-survival MCL-1 and undergo apoptosis in response to single-agent treatment with an MCL-1 inhibitor. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, which is currently the standard of care for this disease, via the stabilization of Noxa and its direct inhibitory binding to MCL-1. BCL-2 inhibition with the FDA-approved inhibitor venetoclax (ABT-199) sensitizes plasma cells to bortezomib treatment and other front-line therapies, which can be observed in vitro and in vivo. Mass spectrometry-based proteomic analysis reveals changes in signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapy. Overall, our results indicate that BH3 mimetics may be highly effective therapies for AL amyloidosis that exploit inherent and induced dependencies on pro-survival proteins.
HostingRepositoryPRIDE
AnnounceDate2023-11-14
AnnouncementXMLSubmission_2023-11-14_08:52:10.695.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMarian Kalocsay
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-02-10 23:49:17ID requested
12022-10-03 10:35:50announced
22023-11-14 08:52:11announced2023-11-14: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: AL amyloidosis BCL-2 apoptosis BH3 bortezomib proteasome inhibition
Contact List
Kristopher Sarosiek
contact affiliationProgram in Molecular and Integrative Physiological Sciences Harvard School of Public Health 665 Huntington Avenue Building 2, Room 221 Boston, MA 02115 USA
contact emailsarosiek@hsph.harvard.edu
lab head
Marian Kalocsay
contact affiliationHarvard Medical School
contact emailmarian_kalocsay@hms.harvard.edu
dataset submitter
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