PXD017292-1

PXD017292 is an original dataset announced via ProteomeXchange.

Title	B-cell-specific MYD88 L252P expression causes a premalignant gammopathy resembling IgM MGUS
Description	A highly recurrent, somatic L265P mutation in the TIR domain of the signaling adapter MYD88 constitutively activates NF-kB. It occurs in nearly all human patients with Waldenström’s macroglobulinemia (WM), a B cell malignancy caused by IgM-expressing cells. Here we introduced an inducible leucine to proline point mutation into the mouse Myd88 locus, at the orthologous position L252P. When the mutation was introduced early during B cell development, B cells developed normally. However, IgM-expressing plasma cells accumulated with age in spleen and bone, leading to more than 20-fold elevated serum IgM titers. When introduced into germinal center B cells in the context of an immunization, the Myd88L252P mutation caused prolonged persistence of antigen-specific serum IgM and elevated numbers of antigen-specific IgM plasma cells. Myd88L252P-expressing B cells switched normally, but plasma cells expressing other immunoglobulin isotypes did not increase in numbers, implying that IgM expression may be required for the observed cellular expansion. In order to test whether the Myd88L252P mutation can cause clonal expansions, we introduced it into a small fraction of CD19-positive B cells. In this scenario, five out of five mice developed monoclonal IgM serum paraproteins accompanied by an expansion of clonally related plasma cells that expressed mostly hypermutated VDJ regions. Taken together, our data suggest that the Myd88L252P mutation is sufficient to promote aberrant survival and expansion of IgM-expressing plasma cells which in turn can cause IgM monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition that precedes WM. References: 1. Shevchenko A, Tomas H, Havli J, Olsen JV, Mann M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc (2006) 1:2856–2860. doi:10.1038/nprot.2006.468, 2. Rappsilber J, Mann M, Ishihama Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc (2007) 2:1896–1906. doi:10.1038/nprot.2007.261, 3. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment. J Proteome Res (2011) 10:1794–1805. doi:10.1021/pr101065j, 4. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol (2008) 26:1367–1372. doi:10.1038/nbt.1511.
HostingRepository	PRIDE
AnnounceDate	2020-11-06
AnnouncementXML	Submission_2020-11-06_06:11:58.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Oliver Popp
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; acetylated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-27 05:27:15	ID requested
⏵ 1	2020-11-06 06:11:58	announced
2	2024-10-22 05:14:40	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: Lymphoid neoplasia

Klaus Rajewsky
contact affiliation	Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
contact email	klaus.rajewsky@mdc-berlin.de
lab head
Oliver Popp
contact affiliation	MDC Berlin
contact email	oliver.popp@mdc-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017292
     1. Label: PRIDE project
     2. Name: B-cell-specific MYD88 L252P expression causes a premalignant gammopathy resembling IgM MGUS