Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis

Peter Leif Bergsagel, W. Michael Kuehl

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Multiple myeloma is a post-germinal centre plasma cell tumour that is usually preceded by a pre-malignant condition, monoclonal gammopathy of undetermined significance. Both are characterized by hyperdiploidy and recurrent immunoglobulin gene translocations that all result in the direct or indirect dysregulation of the CCND/RB1 pathway. Analysis of the translocation breakpoints suggests that they most frequently occur as a result of an error during class switch recombination, but also VDJ recombination, and sometimes somatic hypermutation. A rearrangement of the MYC locus is identified in nearly one half of untreated patients with MM, most frequently (>60 %) those with hyperdiploidy, and less frequently (<25 %) those with t(11;14). The rearrangements juxtapose MYC to super-enhancers from elsewhere in the genome, resulting in dysregulated expression of MYC. One-third of the rearrangements involve an immunoglobulin gene enhancer (IGH > IGL >> IGK), and two-thirds one of a variety of non-immunoglobulin gene enhancers that are frequently associated with plasma cell gene expression (e.g., PRDM1, IGJ, FAM46C, TXNDC5, FOXO3). It is likely that early rearrangements of the MYC locus cause the progression of monoclonal gammopathy to multiple myeloma in many patients, and that late rearrangements of the MYC locus, frequently involving an immunoglobulin gene enhancer, contribute to further, often extramedullary, tumour growth.

Original languageEnglish (US)
Title of host publicationChromosomal Translocations and Genome Rearrangements in Cancer
PublisherSpringer International Publishing
Pages139-156
Number of pages18
ISBN (Electronic)9783319199832
ISBN (Print)9783319199825
DOIs
StatePublished - Jan 1 2015

Fingerprint

Immunoglobulin Genes
Polyploidy
Multiple Myeloma
Immunoglobulins
Genes
V(D)J Recombination
Monoclonal Gammopathy of Undetermined Significance
Paraproteinemias
Germinal Center
Plasmacytoma
Tumors
Plasma Cells
Genetic Recombination
Plasmas
Gene Expression
Gene expression
Growth
Switches
Neoplasms

Keywords

  • Chromosome translocation
  • Monoclonal gammopathy of undetermined significance
  • Multiple myeloma
  • MYC oncogene
  • Plasma cell neoplasm

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bergsagel, P. L., & Kuehl, W. M. (2015). Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis. In Chromosomal Translocations and Genome Rearrangements in Cancer (pp. 139-156). Springer International Publishing. https://doi.org/10.1007/978-3-319-19983-2_8

Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis. / Bergsagel, Peter Leif; Kuehl, W. Michael.

Chromosomal Translocations and Genome Rearrangements in Cancer. Springer International Publishing, 2015. p. 139-156.

Research output: Chapter in Book/Report/Conference proceedingChapter

Bergsagel, PL & Kuehl, WM 2015, Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis. in Chromosomal Translocations and Genome Rearrangements in Cancer. Springer International Publishing, pp. 139-156. https://doi.org/10.1007/978-3-319-19983-2_8
Bergsagel PL, Kuehl WM. Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis. In Chromosomal Translocations and Genome Rearrangements in Cancer. Springer International Publishing. 2015. p. 139-156 https://doi.org/10.1007/978-3-319-19983-2_8
Bergsagel, Peter Leif ; Kuehl, W. Michael. / Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis. Chromosomal Translocations and Genome Rearrangements in Cancer. Springer International Publishing, 2015. pp. 139-156
@inbook{cedbab284f9c434d8cc766bed315436b,
title = "Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis",
abstract = "Multiple myeloma is a post-germinal centre plasma cell tumour that is usually preceded by a pre-malignant condition, monoclonal gammopathy of undetermined significance. Both are characterized by hyperdiploidy and recurrent immunoglobulin gene translocations that all result in the direct or indirect dysregulation of the CCND/RB1 pathway. Analysis of the translocation breakpoints suggests that they most frequently occur as a result of an error during class switch recombination, but also VDJ recombination, and sometimes somatic hypermutation. A rearrangement of the MYC locus is identified in nearly one half of untreated patients with MM, most frequently (>60 {\%}) those with hyperdiploidy, and less frequently (<25 {\%}) those with t(11;14). The rearrangements juxtapose MYC to super-enhancers from elsewhere in the genome, resulting in dysregulated expression of MYC. One-third of the rearrangements involve an immunoglobulin gene enhancer (IGH > IGL >> IGK), and two-thirds one of a variety of non-immunoglobulin gene enhancers that are frequently associated with plasma cell gene expression (e.g., PRDM1, IGJ, FAM46C, TXNDC5, FOXO3). It is likely that early rearrangements of the MYC locus cause the progression of monoclonal gammopathy to multiple myeloma in many patients, and that late rearrangements of the MYC locus, frequently involving an immunoglobulin gene enhancer, contribute to further, often extramedullary, tumour growth.",
keywords = "Chromosome translocation, Monoclonal gammopathy of undetermined significance, Multiple myeloma, MYC oncogene, Plasma cell neoplasm",
author = "Bergsagel, {Peter Leif} and Kuehl, {W. Michael}",
year = "2015",
month = "1",
day = "1",
doi = "10.1007/978-3-319-19983-2_8",
language = "English (US)",
isbn = "9783319199825",
pages = "139--156",
booktitle = "Chromosomal Translocations and Genome Rearrangements in Cancer",
publisher = "Springer International Publishing",

}

TY - CHAP

T1 - Immunoglobulin and MYC rearrangements in multiple myeloma pathogenesis

AU - Bergsagel, Peter Leif

AU - Kuehl, W. Michael

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Multiple myeloma is a post-germinal centre plasma cell tumour that is usually preceded by a pre-malignant condition, monoclonal gammopathy of undetermined significance. Both are characterized by hyperdiploidy and recurrent immunoglobulin gene translocations that all result in the direct or indirect dysregulation of the CCND/RB1 pathway. Analysis of the translocation breakpoints suggests that they most frequently occur as a result of an error during class switch recombination, but also VDJ recombination, and sometimes somatic hypermutation. A rearrangement of the MYC locus is identified in nearly one half of untreated patients with MM, most frequently (>60 %) those with hyperdiploidy, and less frequently (<25 %) those with t(11;14). The rearrangements juxtapose MYC to super-enhancers from elsewhere in the genome, resulting in dysregulated expression of MYC. One-third of the rearrangements involve an immunoglobulin gene enhancer (IGH > IGL >> IGK), and two-thirds one of a variety of non-immunoglobulin gene enhancers that are frequently associated with plasma cell gene expression (e.g., PRDM1, IGJ, FAM46C, TXNDC5, FOXO3). It is likely that early rearrangements of the MYC locus cause the progression of monoclonal gammopathy to multiple myeloma in many patients, and that late rearrangements of the MYC locus, frequently involving an immunoglobulin gene enhancer, contribute to further, often extramedullary, tumour growth.

AB - Multiple myeloma is a post-germinal centre plasma cell tumour that is usually preceded by a pre-malignant condition, monoclonal gammopathy of undetermined significance. Both are characterized by hyperdiploidy and recurrent immunoglobulin gene translocations that all result in the direct or indirect dysregulation of the CCND/RB1 pathway. Analysis of the translocation breakpoints suggests that they most frequently occur as a result of an error during class switch recombination, but also VDJ recombination, and sometimes somatic hypermutation. A rearrangement of the MYC locus is identified in nearly one half of untreated patients with MM, most frequently (>60 %) those with hyperdiploidy, and less frequently (<25 %) those with t(11;14). The rearrangements juxtapose MYC to super-enhancers from elsewhere in the genome, resulting in dysregulated expression of MYC. One-third of the rearrangements involve an immunoglobulin gene enhancer (IGH > IGL >> IGK), and two-thirds one of a variety of non-immunoglobulin gene enhancers that are frequently associated with plasma cell gene expression (e.g., PRDM1, IGJ, FAM46C, TXNDC5, FOXO3). It is likely that early rearrangements of the MYC locus cause the progression of monoclonal gammopathy to multiple myeloma in many patients, and that late rearrangements of the MYC locus, frequently involving an immunoglobulin gene enhancer, contribute to further, often extramedullary, tumour growth.

KW - Chromosome translocation

KW - Monoclonal gammopathy of undetermined significance

KW - Multiple myeloma

KW - MYC oncogene

KW - Plasma cell neoplasm

UR - http://www.scopus.com/inward/record.url?scp=85016789100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016789100&partnerID=8YFLogxK

U2 - 10.1007/978-3-319-19983-2_8

DO - 10.1007/978-3-319-19983-2_8

M3 - Chapter

SN - 9783319199825

SP - 139

EP - 156

BT - Chromosomal Translocations and Genome Rearrangements in Cancer

PB - Springer International Publishing

ER -