PathwayType: signaling

CellType: cancer cell

Notes: Headnote: Multiple myeloma (MM) is a malignancy of isotype-switched, bone marrow-localized plasma cells that manifests in bone destructions, paraprotein production, and bone marrow failure. Signaling description: The primary genetic events that are involved include: 1) in non-hyperdiploid group - translocations between IgH gene and protooncogenes (observed in 60-80% of patients): IGH-MMSET - t(4;14)(p16;q32), IGH-MAF - t(14;16)(q32;q23), IGH-MAFB - t(14;20)(q32;q11), IGH-CCND1 - t(11;14)(q13;q32), IGH-CCND3 - t(6;14)(p21;q32), 2) in hyperdiploid group - trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. All of these events directly or indirectly lead to cyclin D1, 2, and 3 deregulation, which are critical in MM plasma cell proliferation. In addition, the secondary genetic events involved include mutations in NF-kB, TRAF2 and 3, BIRC2, MAP3K14, CYLD, LTBR, TP53, RB2, MYC, TGFR3, NRAS, KRAS, BRAF, CDKN1A, CDKN2C, and other genes which lead to block of apoptosis, cell immortalization, and increased proliferation. The central pathways abnormally activated in MM plasma cells are NF-kB (classical and alternative), JAK/STAT, PI3K/Akt, RAS/MAPK, and NOTCH cascades. In addition, interleukin 6 (IL6), insulin-like growth factor I (IGF1), and vascular endothelial growth factor A (VEGFA) produced by bone marrow stromal cells (BMSCs) and by MM cells are major regulators implicated in MM plasma cells proliferation. Furthermore, the interaction between bone marrow mesenchymal stem cells (BMSCs) and MM plasma cells via ICAM/ITGB2, VCAM/ITGA4, CXCL12 /CXCR4 also plays a critical role in MM cell proliferation. Outcome effects: One of the most prominent features of MM is bone destructions due to osteoclast activation and osteoblast inhibition. Osteoblasts are inhibited by DKK1 and IL3 which are produced by MM cells and osteoclasts. Osteoclasts are activated through TNFSF11/TNFRSF11A, JAG/Notch, and CCL/CCR interaction. Normally, the balance between bone synthesis and resorption is regulated by TNFSF11 and its decoy receptor, TNFRSF11B. In MM bone disease, there is a remarkable imbalance between them with the highly overexpressed TNFSF11 and suppressed TNFRSF11B. TNFSF11 interacts with TNFRSF11A and activates NF-kB, MAPK/FOS-JUN and calcineurin/NFATC1 pathways leading to osteoclast adhesion, activation, fusion, and bone resorption. In conclusion, the overexpression of VEGFA, IGF1, HGF, and IL6 by MM plasma cells and BMSCs leads to the increased vascularization of the tumor. Highlighted proteins: Proteins with increased expression or activity are highlighted in red, and proteins with decreased expression or activity are highlighted in blue.

Tissue: bone marrow

PMID: 17351339

PMID: 21378363

PMID: 16917004

PMID: 20890394

PMID: 20430962

PMID: 21652011

CellType: plasma cell

NodeType: Pathway

CellType: osteoblast

Organ_System: skeletal system

Pathway_Author: S. Sozin www.researchgate.net/profile/Sergey-Sozin

CellType: osteoclast

PMID: 23023717

Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-ff0a30b6-617e-410c-a940-64b9b51b7905

PMID: 16239913

Description: Multiple myeloma (MM) is a malignancy of isotype-switched, bone marrow-localized plasma cells that manifests in bone destructions, paraprotein production, and bone marrow failure. Pathway is built manually using published studies.

CellType: bone marrow stromal cell

PMID: 21411443

PMID: 20416379

Source: Diseases

urn:agi-pathway:uuid-ff0a30b6-617e-410c-a940-64b9b51b7905