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  • Review Article
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Multiple myeloma: evolving genetic events and host interactions

Key Points

  • Multiple myeloma, which is located at multiple sites in the bone-marrow compartment, is a malignant plasma-cell tumour that is characterized by osteolytic bone lesions. It is a slowly proliferating tumour, typically with less than 1% of tumour cells synthesizing DNA, until late in the disease, when multiple myeloma cells are often found outside the bone marrow.

  • A pre-malignant lesion called monoclonal gammopathy of undetermined significance (MGUS), which is present in 1% of adults, progresses to malignant multiple myeloma at a rate of 1% per year.

  • The karyotypes of multiple myeloma are complex, and more similar to those found in epithelial tumours and the blast phase of chronic myelogenous leukaemia than to those in other haematopoietic tumours.

  • Primary translocations — mediated by errors in B-cell-specific DNA modification processes — juxtapose one or more oncogenes and immunoglobulin transcriptional regulatory regions in 50% of MGUS and multiple myelomas. In contrast to other B-cell malignancies, these translocations simultaneously dysregulate a variety of oncogenes, such as the genes for cyclin D1 or D3, fibroblast growth factor receptor 3 (FGFR3) combined with the nuclear protein MMSET, and the transcription factor c-MAF.

  • Secondary translocations that do not involve B-cell-specific processes contribute to progression by dysregulating other oncogenes. Although c-MYC is dysregulated by primary translocations in some B-cell malignancies, it is dysregulated by secondary translocations, often without involvement of an immunogloublin locus, as myeloma tumours become more proliferative at a late stage of progression.

  • Genetic changes are similar in pre-malignant MGUS and multiple myeloma, although the latter is distinguished by the presence of activating mutations of NRAS or KRAS2, and also a higher incidence of monosomy 13, indicating a possible tumour-suppressor gene on chromosome 13.

  • Normal plasma cells, as well as MGUS and multiple myeloma cells, are dependent on the bone-marrow microenvironment for survival, growth and differentiation. These processes are, in part, mediated by paracrine interleukin-6 and insulin-like growth factor 1. The evolving interaction of multiple myeloma cells with the bone-marrow microenvironment is also involved in the secondary effects of malignancy, including osteolysis, anaemia and immunodeficiency.

  • Multiple myeloma is an incurable malignancy for which the median survival has remained fixed at about 3 years for the past decade. Although MGUS can be efficiently diagnosed by a simple blood test, it is not possible to prevent progression or even predict when progression to myeloma will occur. Recent advances in understanding the molecular pathogenesis of these tumours indicate that improved approaches for prevention and treatment should be possible in the near future.

Abstract

Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?

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Figure 1: Stages of multiple myeloma.
Figure 2: Examples of simple and complex translocations in multiple myeloma.
Figure 3: The bone-marrow microenvironment in multiple myeloma.
Figure 4: Molecular pathogenesis of myeloma.

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Acknowledgements

The authors would like to thank S. Ely for providing the histology pictures in Figure 1, members of their labs who contributed unpublished data, and numerous other colleagues with whom they have discussed many of the issues covered in this review.

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DATABASES

CancerNet:

Burkitt's lymphoma

chronic lymphocytic leukaemia

chronic myelogenous leukaemia

colon cancer

multiple myeloma

 LocusLink:

AKT

BAD

BCLX L

bFGF

CD19

CD38

CD45

CDKN2A

c-MAF

cyclin D1

cyclin D2

cyclin D3

FGFR3

HGF

HRAS

IGF1

IL-1β

IL-6

IL-6R

α4β1 integrin

KRAS2

Ku80

MAFB

MAPK

MCL1

MIP-1α

MLL1

MMSET

NRAS

nuclear factor-κB

OPG

p53

PI3K

PIM1

PTEN

PTHrP

RANK

RANKL

RB

SDF1

STAT3

TGF-β

TNF-α

VCAM1

VEGF

WWOX

 Medscape DrugInfo:

prednisone

lovastatin

melphalan

thalidomide

FURTHER INFORMATION

International Myeloma Foundation

Lambert Laboratory of Myeloma Genetics, University of Arkansas for Medical Sciences

Leukemia and Lymphoma Society

Microarray expression data:Institut national de la sante et de la recherche medicale, Montpellier, France

Multiple Myeloma Research Foundation

Multiple Myeloma Research Web Server

NCI Lymphochip data

Glossary

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

The presence of a stable, low level of monoclonal immunoglobulin in the serum or urine of persons with less than 10% plasma cells in the bone marrow and no evidence of multiple myeloma, amyloidosis, Waldenstrom's macroglobulinaemia or related disorder.

AMYLOIDOSIS

A heterogeneous group of disorders associated with extracellular deposition of protein in a characterisitic fibrillar form. Amyloid fibrils are derived from monoclonal immunoglobulin light chains and most affected individuals die of heart failure, renal failure or some other effect of amyloid within 6–18 months of diagnosis.

INTRAMEDULLARY SITE

Site of disease that is confined to the bone marrow, which is by far the most common location.

SMOULDERING MYELOMA

Has a stable intramedullary tumour content of greater than 10% with none of the malignant features of multiple myeloma.

EXTRAMEDULLARY SITE

Site of disease outside the bone marrow, such as blood, pleural fluid and skin.

PLASMA-CELL LEUKAEMIA

Diagnosed when greater than 20% of the white blood cells are malignant plasma cells.

PLASMA-CELL LABELLING INDEX

The percentage of plasma cells in a tumour specimen that incorporate a DNA precursor during a 30-minute in vitro incubation, thereby providing some measure of the fraction of tumour cells that are involved in proliferation.

BALANCED TRANSLOCATION

A simple reciprocal translocation that generates two derivative chromosomes with no apparent loss (or gain) of sequences from either chromosome.

UNBALANCED TRANSLOCATION

A translocation that generates a derivative chromosome(s) that has lost sequences from the involved chromosomes (sometimes more than two).

COMPARATIVE GENOMIC HYBRIDIZATION

(CGH). This uses two sources of genomic DNA (typically from tumour and normal cells) that are differentially labelled with unique fluors, mixed and then hybridized to normal chromosomes. The ratio of signals reflects the representation of DNA sequences at different chromosomal locations in the two samples.

SPECTRAL KARYOTYPING

(SKY). Simultaneous visualization of an organism's chromosomes, each labelled with a different colour. This technique is useful for identifying chromosome abnormalities.

HYPODIPLOIDY/HYPERDIPLOIDY

A loss or gain of chromosome number or DNA content compared with a normal diploid cell.

PRIMARY TRANSLOCATION

Translocations that occur as the early, perhaps initiating, event in tumorigenesis.

SECONDARY TRANSLOCATION

Translocations that occur during tumour progression.

ENHANCER

A cis-acting sequence that increases the use of (some) promoters, and can function in either orientation and in any location relative to a promoter.

GERMINAL CENTRE

Follicular cell structure in secondary lymphoid tissues in which antigen-driven B-cell maturation occurs.

FLUORESCENCE IN SITU HYBRIDIZATION

(FISH). Uses one or more probes (chromosome, region, gene or sub-gene specific) that are differentially labelled with fluors and then hybridized to metaphase chromosomes or interphase nuclei so that the numbers and locations of different sequences can be assessed in individual cells.

SET DOMAIN

A protein domain that was first described in the Drosophila proteins Su(var)3-9, Enhancer of Zeste and Trithorax. Proteins with SET domains are thought to be involved in chromatin remodelling. MMSET, and MLL1 on 11q23, are mammalian SET domain proteins that are dysregulated by chromosome translocations.

B-ZIP TRANSCRIPTION FACTOR

Transcription factor that has a basic and a leucine zipper domain. The best characterized are the AP1 factors c-JUN and c-FOS.

FRAGILE SITE

An area of chromosome breakage that can be induced by exposure to inhibitors of DNA replication, such as aphidicolin. FRA16D (WWOX) and FRA3B (FHIT) are the most frequently expressed among more than 80 commonly described sites.

INTERSTITIAL DELETION

An internal deletion of a chromosome of varying size that might not be identified by traditional G-banding techniques.

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Kuehl, W., Bergsagel, P. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2, 175–187 (2002). https://doi.org/10.1038/nrc746

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