Msh2-dependent DNA repair mitigates a unique susceptibility of B cell progenitors to c-Myc-induced lymphomas

Rajeev M. Nepal, Li Tong, Blerta Kolaj, Winfried Edelmann, Alberto Martin

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

C-Myc is one of the most common targets of genetic alterations in human cancers. Although overexpression of c-Myc in the B cell compartment predisposes to lymphomas, secondary mutations are required for disease manifestation. In this article, we show that genetic deficiencies causing arrested B cell development and accumulation of B cell progenitors lead to accelerated lymphomagenesis in Eμ c-myc transgenic mice. This result suggests that B cell progenitors are more prone than their mature counterparts to developing secondary oncogenic lesions that complement c-Myc in promoting transformation. To investigate the nature of these oncogenic lesions, we examined Eμ c-myc mice deficient in mismatch repair function. We report that Msh2 G674A/G674A Eμ c-myc and Msh2G674A/G674A Eμ c-myc mice rapidly succumb to pro-B cell stage lymphomas, indicating that Msh2-dependent mismatch repair function actively suppresses c-Myc-associated oncogenesis during early B cell development.

Original languageEnglish (US)
Pages (from-to)18698-18703
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number44
DOIs
StatePublished - Nov 3 2009

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B-Lymphoid Precursor Cells
DNA Repair
Lymphoma
DNA Mismatch Repair
B-Lymphocytes
B-Cell Lymphoma
Transgenic Mice
Carcinogenesis
Mutation
Neoplasms

Keywords

  • Apoptosis
  • Mismatch repair
  • Oncogenesis
  • p53

ASJC Scopus subject areas

  • General

Cite this

Msh2-dependent DNA repair mitigates a unique susceptibility of B cell progenitors to c-Myc-induced lymphomas. / Nepal, Rajeev M.; Tong, Li; Kolaj, Blerta; Edelmann, Winfried; Martin, Alberto.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 44, 03.11.2009, p. 18698-18703.

Research output: Contribution to journalArticle

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AU - Edelmann, Winfried

AU - Martin, Alberto

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N2 - C-Myc is one of the most common targets of genetic alterations in human cancers. Although overexpression of c-Myc in the B cell compartment predisposes to lymphomas, secondary mutations are required for disease manifestation. In this article, we show that genetic deficiencies causing arrested B cell development and accumulation of B cell progenitors lead to accelerated lymphomagenesis in Eμ c-myc transgenic mice. This result suggests that B cell progenitors are more prone than their mature counterparts to developing secondary oncogenic lesions that complement c-Myc in promoting transformation. To investigate the nature of these oncogenic lesions, we examined Eμ c-myc mice deficient in mismatch repair function. We report that Msh2 G674A/G674A Eμ c-myc and Msh2G674A/G674A Eμ c-myc mice rapidly succumb to pro-B cell stage lymphomas, indicating that Msh2-dependent mismatch repair function actively suppresses c-Myc-associated oncogenesis during early B cell development.

AB - C-Myc is one of the most common targets of genetic alterations in human cancers. Although overexpression of c-Myc in the B cell compartment predisposes to lymphomas, secondary mutations are required for disease manifestation. In this article, we show that genetic deficiencies causing arrested B cell development and accumulation of B cell progenitors lead to accelerated lymphomagenesis in Eμ c-myc transgenic mice. This result suggests that B cell progenitors are more prone than their mature counterparts to developing secondary oncogenic lesions that complement c-Myc in promoting transformation. To investigate the nature of these oncogenic lesions, we examined Eμ c-myc mice deficient in mismatch repair function. We report that Msh2 G674A/G674A Eμ c-myc and Msh2G674A/G674A Eμ c-myc mice rapidly succumb to pro-B cell stage lymphomas, indicating that Msh2-dependent mismatch repair function actively suppresses c-Myc-associated oncogenesis during early B cell development.

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