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MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells

MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells
MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells
Background:

The recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear.

Design and Methods:

The expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays.

Results:

We found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples.

Conclusions:

In conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival.
MMSET, WHSC1, myeloma
0390-6078
78-86
Brito, Jose L.R.
cd717b2e-c219-4fb8-9d86-897507bc90fa
Walker, Brian
86b9da7d-322f-4573-bb53-a0811ae2881c
Jenner, Matthew
ea34e192-4eea-4f1c-938c-bd6799ebd963
Dickens, Nicholas J.
a22b3b23-76ab-493a-b34e-669a2c3ee1c4
Brown, Nicola J.M.
6daa7ee1-0fe8-411b-8ea4-5f666102fb7b
Ross, Fiona M.
ec0958f8-b992-4e4a-b7e3-c474600390ba
Avramidou, Athanasia
d29c4240-9517-447b-8e5a-1c26526560e2
Irving, Julie A.E.
316841b5-d102-4a28-b4dc-6503aeb832e0
Gonzalez, David
23765c4d-1658-40fd-a487-bc11bad2aea3
Davies, Faith E.
9ea9e143-ac51-431b-8cb5-57b8dc0a38af
Morgan, Gareth J.
d285dcf8-ac2c-4fe0-acf9-4787eb025939
Brito, Jose L.R.
cd717b2e-c219-4fb8-9d86-897507bc90fa
Walker, Brian
86b9da7d-322f-4573-bb53-a0811ae2881c
Jenner, Matthew
ea34e192-4eea-4f1c-938c-bd6799ebd963
Dickens, Nicholas J.
a22b3b23-76ab-493a-b34e-669a2c3ee1c4
Brown, Nicola J.M.
6daa7ee1-0fe8-411b-8ea4-5f666102fb7b
Ross, Fiona M.
ec0958f8-b992-4e4a-b7e3-c474600390ba
Avramidou, Athanasia
d29c4240-9517-447b-8e5a-1c26526560e2
Irving, Julie A.E.
316841b5-d102-4a28-b4dc-6503aeb832e0
Gonzalez, David
23765c4d-1658-40fd-a487-bc11bad2aea3
Davies, Faith E.
9ea9e143-ac51-431b-8cb5-57b8dc0a38af
Morgan, Gareth J.
d285dcf8-ac2c-4fe0-acf9-4787eb025939

Brito, Jose L.R., Walker, Brian, Jenner, Matthew, Dickens, Nicholas J., Brown, Nicola J.M., Ross, Fiona M., Avramidou, Athanasia, Irving, Julie A.E., Gonzalez, David, Davies, Faith E. and Morgan, Gareth J. (2009) MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells. Haematologica, 94 (1), 78-86. (doi:10.3324/haematol.13426).

Record type: Article

Abstract

Background:

The recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear.

Design and Methods:

The expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays.

Results:

We found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples.

Conclusions:

In conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival.

Full text not available from this repository.

More information

Published date: 4 December 2009
Keywords: MMSET, WHSC1, myeloma

Identifiers

Local EPrints ID: 153161
URI: https://eprints.soton.ac.uk/id/eprint/153161
ISSN: 0390-6078
PURE UUID: 3a17f50f-3c75-482c-b575-e13e2e941c0b

Catalogue record

Date deposited: 19 May 2010 08:30
Last modified: 16 Jul 2019 23:59

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Contributors

Author: Jose L.R. Brito
Author: Brian Walker
Author: Matthew Jenner
Author: Nicholas J. Dickens
Author: Nicola J.M. Brown
Author: Fiona M. Ross
Author: Athanasia Avramidou
Author: Julie A.E. Irving
Author: David Gonzalez
Author: Faith E. Davies
Author: Gareth J. Morgan

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