Germinal center B-cells resist transformation by Kras independently of tumor suppressor Arf

Chelsea D Mullins; Mack Y Su; Vishwanathan Hucthagowder; Liang Chu; Lan Lu; Shashikant Kulkarni; Deborah Novack; Ravi Vij; Michael H Tomasson

doi:10.1371/journal.pone.0067941

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Germinal center B-cells resist transformation by Kras independently of tumor suppressor Arf

Journal article

Open access

Peer reviewed

Germinal center B-cells resist transformation by Kras independently of tumor suppressor Arf

Chelsea D Mullins, Mack Y Su, Vishwanathan Hucthagowder, Liang Chu, Lan Lu, Shashikant Kulkarni, Deborah Novack, Ravi Vij and Michael H Tomasson

PloS one, Vol.8(6), pp.e67941-e67941

2013

DOI: 10.1371/journal.pone.0067941

PMCID: PMC3692489

PMID: 23825691

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Abstract

Activating mutations in Ras (N- and K-) are the most common point mutations found in patients with multiple myeloma (MM) and are associated with poor clinical outcome. We sought to directly examine the role of Ras activation in MM pathogenesis and used two different tissue-specific Cre recombinase mouse lines (Cγ1-Cre and AID-Cre), to generate mice with mutant Kras (Kras(G12D) ) activated specifically in germinal center B-cells. We also generated mice with activation of the Kras(G12D) allele in a tumor-prone Arf-null genetic background. Surprisingly, we observed no significant disruption in B-cell homeostasis in any of these models by serum immunoglobulin ELISA, SPEP, flow cytometry and histological examination. We observed development of non-overlapping tumor types due to off-target Cre expression, but despite successful recombination in germinal center and later B-cell populations, we observed no B-cell phenotype. Together, these data demonstrate that Ras activation is not sufficient to transform primary germinal center B-cells, even in an Arf-null context, and that the temporal order of mutation acquisition may be critical for myeloma development. Specific pathways, yet to be identified, are required before Kras can contribute to the development of MM.

Skin Neoplasms - pathology

ras Proteins - genetics

Cyclin-Dependent Kinase Inhibitor p16 - deficiency

Proto-Oncogene Proteins p21(ras)

Germinal Center - immunology

Cyclin-Dependent Kinase Inhibitor p16 - genetics

Mice, Transgenic

Proto-Oncogene Proteins - genetics

Animals

Cell Transformation, Neoplastic

Tumor Suppressor Proteins - deficiency

Gene Deletion

Tumor Suppressor Proteins - genetics

Lymphoma - pathology

Papilloma - pathology

Mice

B-Lymphocytes - pathology

Thymoma - pathology

Details

Title: Subtitle: Germinal center B-cells resist transformation by Kras independently of tumor suppressor Arf
Creators: Chelsea D Mullins - Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America
Mack Y Su
Vishwanathan Hucthagowder
Liang Chu
Lan Lu
Shashikant Kulkarni
Deborah Novack
Ravi Vij
Michael H Tomasson
Resource Type: Journal article
Publication Details: PloS one, Vol.8(6), pp.e67941-e67941
DOI: 10.1371/journal.pone.0067941
PMID: 23825691
PMCID: PMC3692489
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: R21AG040777 / NIA NIH HHS R21 AG040777 / NIA NIH HHS
Language: English
Date published: 2013
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094568902771

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