Human Disease Model Report: multiple myeloma, DIS3-related

General Information

Name

multiple myeloma, DIS3-related

FlyBase ID

FBhh0000835

Disease Ontology Term

multiple myeloma

Parent Disease

OMIM

MYELOMA, MULTIPLE

Overview

The mitotic control gene DIS3 has been found to be one of the most frequently mutated genes in multiple myeloma patients. DIS3 is a component of the RNA exosome complex, participating in many cellular RNA processing and degradation events. Relevant to multiple myeloma, the RNA exosome may be involved in Ig class switch recombination. There is a single orthologous gene in Drosophila, Dis3, for which classical amorphic alleles, RNAi-targeting constructs, and an allele caused by insertional mutagenesis have been generated.

The human DIS3 gene has not been introduced into flies.

Work in flies has pinpointed an important distinction in Dis3 disease-related phenotypes: reduction, but not elimination, of Dis3 function can enhance cell proliferation. In Drosophila, elimination or strong reduction of Dis3 function (specifically of its exonuclease activity) inhibits mitotic cell division. However, as initially observed in ovary follicle cells, mild reduction of Dis3 function enhances cell proliferation in the presence of elevated Ras-ERK signaling activity in some tissues. Multiple physical and genetic interactions have been described for Dmel\Dis3; see below and in the Dis3 gene report.

[updated Jul. 2018 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: multiple myeloma, DIS3-related

OMIM report

[MYELOMA, MULTIPLE](https://omim.org/entry/254500)

Human gene(s) implicated

[CYCLIN D1; CCND1](https://omim.org/entry/168461)

[LIGASE IV, DNA, ATP-DEPENDENT; LIG4](https://omim.org/entry/601837)

Symptoms and phenotype

Multiple myeloma is a neoplastic plasma cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction (Palumbo and Anderson, 2011; pubmed:21410373). [from MIM:254500; 2018.07.06]

(OMIM, 2013-)

Genetics

In multiple studies of aberrant genes in multiple myeloma patients, mutations of DIS3 have been detected (Chapman et al., 2011, pubmed:21430775; Lohr et al., 2014; pubmed:24434212).

(FlyBase Curators, 2013-)

Several chromosome aberrations, including recurrent translocations and deletions, have been found to be related to the development or progression of multiple myeloma. [from MIM:254500; 2018.07.06]

(OMIM, 2013-)

Cellular phenotype and pathology

Myeloma arises from an asymptomatic premalignant proliferation of monoclonal plasma cells that are derived from post-germinal-center B cells. Multistep genetic and microenvironmental changes lead to the transformation of these cells into a malignant neoplasm. The diagnosis of myeloma is based on the presence of at least 10% clonal bone marrow plasma cells and monoclonal antibody protein in serum or urine. (Palumbo and Anderson, 2011; pubmed:21410373)

(FlyBase Curators, 2013-)

Molecular information

DIS3 has both 3-5 exonuclease and endonuclease activities; it is a putative exonuclease catalytic component of the RNA exosome complex which participates in a multitude of cellular RNA processing and degradation events. The RNA exosome may be involved in Ig class switch recombination and/or Ig variable region somatic hypermutation. [Gene Cards, DIS3; 2018.07.06]

(FlyBase Curators, 2013-)

The RNA exosome is a 3'-5' exonuclease complex present in the nucleus and cytoplasm that can process and degrade many types of RNAs, including mRNA, rRNA, snRNA, snoRNA and tRNA (FBgg0000597).

(FlyBase Curators, 2013-)

External links

COSMIC gene: DIS3
Gene2Function (human gene): DIS3
Gene Cards: DIS3
MedlinePlus (condition): Multiple myeloma
MedlinePlus (gene): DIS3
MARRVEL (human gene): DIS3
NCBI MedGen: Multiple myeloma (MM)
NCBI (Entrez) gene: DIS3; DIS3 exosome endoribonuclease and 3'-5' exoribonuclease

Disease synonyms

monoclonal gammopathy

Related Diseases

Related human health report(s)

cancer, general (fly models overview)

hematologic cancer (fly models overview)

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

DIS3; DIS3 exosome endoribonuclease and 3'-5' exoribonuclease

D. melanogaster ortholog (based on DIOPT)

Dmel\Dis3

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Dis3

Gene Snapshot

Dis3 (Dis3) encodes an exoribonuclease that forms part of the RNA processing exosome complex. It is involved in the regulation of cell cycle progresion, microRNA expression and mRNA surveillance. [Date last reviewed: 2019-09-12]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human DIS3 (1 Drosophila to 1 human). Dmel\Dis3 shares 55% identity and 71% similarity with the human gene.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (14 groups)

Dis3

protein-protein

Interacting group

Assay

References

Dis3 - Csl4

anti tag coimmunoprecipitation, western blot, experimental knowledge based

(Guruharsha et al., 2011, Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Kap-α3

anti tag coimmunoprecipitation, Identification by mass spectrometry, western blot

(Mamolen et al., 2010, Graham et al., 2009)

Dis3 - mof

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Mendjan et al., 2006)

Dis3 - msl-3

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Mendjan et al., 2006)

Dis3 - Mtr3

experimental knowledge based, anti tag coimmunoprecipitation, western blot

(Guruharsha et al., 2011, Graham et al., 2009)

Dis3 - Otud6

anti tag coimmunoprecipitation, Identification by mass spectrometry, western blot

(Villa et al., 2024)

Dis3 - Rrp4

anti tag coimmunoprecipitation, western blot, experimental knowledge based

(Guruharsha et al., 2011, Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Rrp6

experimental knowledge based, anti tag coimmunoprecipitation, western blot

(Guruharsha et al., 2011, Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Rrp40

anti tag coimmunoprecipitation, western blot

(Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Rrp42

anti tag coimmunoprecipitation, western blot, experimental knowledge based

(Guruharsha et al., 2011, Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Rrp45

anti tag coimmunoprecipitation, western blot

(Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Rrp46

anti tag coimmunoprecipitation, western blot

(Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Rrp47

anti tag coimmunoprecipitation, western blot

(Mamolen et al., 2010, Graham et al., 2009)

Dis3 - Ski6

experimental knowledge based, anti tag coimmunoprecipitation, western blot

(Guruharsha et al., 2011, Mamolen et al., 2010)

Alleles Reported to Model Human Disease (Disease Ontology) (6 alleles)

Dis3

Models Based on Experimental Evidence ( 4 )

Allele

Disease

Evidence

References

Dis3^KK101473

model of multiple myeloma

CEA

(Snee et al., 2016)

Dis3¹

model of multiple myeloma

CEA

(Snee et al., 2016)

Dis3²

model of multiple myeloma

CEA

(Snee et al., 2016)

Dis3^HMS05761

model of primary ovarian insufficiency

CEA

(Kline et al., 2025, Johnstone et al., 2023)

Modifiers Based on Experimental Evidence ( 4 )

Allele

Disease

Interaction

References

Dis3^G5039

ameliorates multiple myeloma

modeled by Dis3¹

(Snee et al., 2016)

Dis3¹

model of multiple myeloma

is ameliorated by Dis3^G5039

(Snee et al., 2016)

Dis3^HMS05761

model of primary ovarian insufficiency

is ameliorated by Hsap\DIS3^UAS.cKa

(Kline et al., 2025)

Dis3^HMJ24000

exacerbates cancer

modeled by Rbf^HMS03004

(Parkhitko et al., 2021)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Dis3^HMJ24000

P{TRiP.HMJ24000}

y¹ v¹; P{TRiP.HMJ24000}attP40/CyO

Dis3^GD11917

P{GD11917}

w¹¹¹⁸; P{GD11917}v35090

y¹ sc^* v¹ sev²¹; P{TRiP.HMS05761}attP40

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Dis3^G5039

P-element activity

w¹¹¹⁸; P{EP}Dis3^G5039

Dis3¹