B-cell maturation antigen

B-cell maturation antigen (BCMA or BCM), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein that in humans is encoded by the TNFRSF17 gene.

TNFRSF17
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OQD, 1XU2, 2KN1, 4ZFO
Identifiers
Aliases	TNFRSF17, BCM, BCMA, CD269, TNFRSF13A, tumor necrosis factor receptor superfamily member 17, TNF receptor superfamily member 17
External IDs	OMIM: 109545 MGI: 1343050 HomoloGene: 920 GeneCards: TNFRSF17
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p13.13 Start 11,965,210 bp[1] End 11,968,068 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16|16 A1 Start 11,313,812 bp[2] End 11,320,074 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • signaling receptor activity Cellular component • endomembrane system • cell membrane • membrane • integral component of membrane Biological process • multicellular organism development • tumor necrosis factor-mediated signaling pathway • lymphocyte homeostasis • cellular proliferation • immune system process • adaptive immune response • signal transduction Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	608	21935
Ensembl	ENSG00000048462	ENSMUSG00000022496
UniProt	Q02223	O88472
RefSeq (mRNA)	NM_001192	NM_011608
RefSeq (protein)	NP_001183	NP_035738
Location (UCSC)	Chr 16: 11.97 – 11.97 Mb	Chr 16: 11.31 – 11.32 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

BCMA TALL-1 binding domain
crystal structure of stall-1 and bcma
Identifiers
Symbol	BCMA-Tall_bind
Pfam	PF09257
InterPro	IPR015337
SCOP2	1oqd / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

TNFRSF17 is a cell surface receptor of the TNF receptor superfamily which recognizes B-cell activating factor (BAFF).[5][6][7]

Function

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is preferentially expressed in mature B lymphocytes, and may be important for B cell development and autoimmune response. This receptor has been shown to specifically bind to the tumor necrosis factor (ligand) superfamily, member 13b (TNFSF13B/TALL-1/BAFF), and to lead to NF-kappaB and MAPK8/JNK activation. This receptor also binds to various TRAF family members, and thus may transduce signals for cell survival and proliferation.[7]

Interactions

TNFRSF17 has been shown to interact with the B-cell activating factor TNFSF13B.[8][9] A conserved domain at the N-terminus, BCMA TALL-1 binding domain, is required for binding to the TNFSF13B.[8]

Clinical significance - Related Diseases

TNFRSF17 is implicated in leukemia, lymphomas, and multiple myeloma [10] (see the "Mitelman Database" [11] and the Atlas of Genetics and Cytogenetics in Oncology and Haematology,[12]).

As a drug target

An antibody-drug conjugate GSK2857916 (belantamab mafodotin) demonstrated activity in patients with relapsed/refractory multiple myeloma, previously treated with an immunomodulatory drug, proteosome inhibitor, or who were intolerant/refractory to an anti-CD38 monoclonal antibody. The primary toxicities were keratopathy, thrombocytopenia, and anemia.[13]

Belantamab mafodotin (GSK2857916) was approved for medical use in the United States in August 2020.[14][15]

A Phase 1b/2 study of CAR-T cell therapy directed against BCMA in myeloma patients refractory to a proteasome inhibitor or immunomodulatory drug, and who had received an anti-CD38 antibody showed a 91% overall response rate. Main toxicities were cytokine release syndrome and cytopenias.[16]

References

1. GRCh38: Ensembl release 89: ENSG00000048462 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022496 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Laâbi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, Larsen CJ, Tsapis A (November 1992). "A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma". The EMBO Journal. 11 (11): 3897–904. doi:10.1002/j.1460-2075.1992.tb05482.x. PMC 556899. PMID 1396583.
6. Laabi Y, Gras MP, Brouet JC, Berger R, Larsen CJ, Tsapis A (April 1994). "The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed". Nucleic Acids Research. 22 (7): 1147–54. doi:10.1093/nar/22.7.1147. PMC 523635. PMID 8165126.
7. "Entrez Gene: TNFRSF17 tumor necrosis factor receptor superfamily, member 17".
8. Liu Y, Hong X, Kappler J, Jiang L, Zhang R, Xu L, et al. (May 2003). "Ligand-receptor binding revealed by the TNF family member TALL-1". Nature. 423 (6935): 49–56. Bibcode:2003Natur.423...49L. doi:10.1038/nature01543. PMID 12721620. S2CID 4373708.
9. Shu HB, Johnson H (August 2000). "B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1". Proceedings of the National Academy of Sciences of the United States of America. 97 (16): 9156–61. Bibcode:2000PNAS...97.9156S. doi:10.1073/pnas.160213497. PMC 16838. PMID 10908663.
10. "TNFRSF17 (tumor necrosis factor receptor superfamily, member 17)". atlasgeneticsoncology.org.
11. "Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer".
12. "Atlas of Genetics and Cytogenetics in Oncology and Haematology". atlasgeneticsoncology.org.
13. Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, et al. (February 2020). "Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study". The Lancet. Oncology. 21 (2): 207–221. doi:10.1016/s1470-2045(19)30788-0. PMID 31859245.
14. "FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma". U.S. Food and Drug Administration (FDA). 5 August 2020. Retrieved 6 August 2020. This article incorporates text from this source, which is in the public domain.
15. "FDA Approves GSK's BLENREP (belantamab mafodotin-blmf) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma" (Press release). GlaxoSmithKline. 6 August 2020. Retrieved 6 August 2020 – via Business Wire.
16. Madduri D, Usmani SZ, Jagannath S, Singh I, Zudaire E, Yeh TM, et al. (2019-11-13). "Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM)". Blood. 134 (Supplement_1): 577. doi:10.1182/blood-2019-121731. ISSN 0006-4971.

External links

• Human TNFRSF17 genome location and TNFRSF17 gene details page in the UCSC Genome Browser.

Further reading

• Treml LS, Crowley JE, Cancro MP (October 2006). "BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells". Seminars in Immunology. 18 (5): 297–304. doi:10.1016/j.smim.2006.07.001. PMID 16919470.
• Mackay F, Leung H (October 2006). "The role of the BAFF/APRIL system on T cell function". Seminars in Immunology. 18 (5): 284–9. doi:10.1016/j.smim.2006.04.005. PMID 16931039.
• Gras MP, Laâbi Y, Linares-Cruz G, Blondel MO, Rigaut JP, Brouet JC, et al. (July 1995). "BCMAp: an integral membrane protein in the Golgi apparatus of human mature B lymphocytes". International Immunology. 7 (7): 1093–106. doi:10.1093/intimm/7.7.1093. PMID 8527407.
• Loftus BJ, Kim UJ, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, et al. (September 1999). "Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q". Genomics. 60 (3): 295–308. doi:10.1006/geno.1999.5927. PMID 10493829.
• Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, et al. (April 2000). "TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease". Nature. 404 (6781): 995–9. Bibcode:2000Natur.404..995G. doi:10.1038/35010115. PMID 10801128. S2CID 4323357.
• Hatzoglou A, Roussel J, Bourgeade MF, Rogier E, Madry C, Inoue J, et al. (August 2000). "TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase". Journal of Immunology. 165 (3): 1322–30. doi:10.4049/jimmunol.165.3.1322. PMID 10903733.
• Shu HB, Johnson H (August 2000). "B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1". Proceedings of the National Academy of Sciences of the United States of America. 97 (16): 9156–61. Bibcode:2000PNAS...97.9156S. doi:10.1073/pnas.160213497. PMC 16838. PMID 10908663.
• Yu G, Boone T, Delaney J, Hawkins N, Kelley M, Ramakrishnan M, et al. (September 2000). "APRIL and TALL-I and receptors BCMA and TACI: system for regulating humoral immunity". Nature Immunology. 1 (3): 252–6. doi:10.1038/79802. PMID 10973284. S2CID 6799584.
• Kawasaki A, Tsuchiya N, Fukazawa T, Hashimoto H, Tokunaga K (August 2001). "Presence of four major haplotypes in human BCMA gene: lack of association with systemic lupus erythematosus and rheumatoid arthritis". Genes and Immunity. 2 (5): 276–9. doi:10.1038/sj.gene.6363770. PMID 11528522.
• Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, et al. (January 2004). "Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival". Blood. 103 (2): 689–94. doi:10.1182/blood-2003-06-2043. PMID 14512299.
• Hymowitz SG, Patel DR, Wallweber HJ, Runyon S, Yan M, Yin J, et al. (February 2005). "Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding". The Journal of Biological Chemistry. 280 (8): 7218–27. doi:10.1074/jbc.M411714200. PMID 15542592.
• Bellucci R, Alyea EP, Chiaretti S, Wu CJ, Zorn E, Weller E, et al. (May 2005). "Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor". Blood. 105 (10): 3945–50. doi:10.1182/blood-2004-11-4463. PMC 1895080. PMID 15692072.
• Hendriks J, Planelles L, de Jong-Odding J, Hardenberg G, Pals ST, Hahne M, et al. (June 2005). "Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation". Cell Death and Differentiation. 12 (6): 637–48. doi:10.1038/sj.cdd.4401647. PMID 15846369.
• Chiu A, Xu W, He B, Dillon SR, Gross JA, Sievers E, et al. (January 2007). "Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL". Blood. 109 (2): 729–39. doi:10.1182/blood-2006-04-015958. PMC 1785096. PMID 16960154.
• Smirnova AS, Andrade-Oliveira V, Gerbase-DeLima M (February 2008). "Identification of new splice variants of the genes BAFF and BCMA". Molecular Immunology. 45 (4): 1179–83. doi:10.1016/j.molimm.2007.07.028. PMID 17825416.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This article incorporates text from the public domain Pfam and InterPro: IPR015337