Apurinic/apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge

Jeroen E.J. Guikema, Rachel M. Gerstein, Erin K. Linehan, Erin K. Cloherty, Eric Evan-Browning, Daisuke Tsuchimoto, Yusaku Nakabeppu, Carol E. Schrader

Research output: Contribution to journalArticle

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Abstract

B cell development involves rapid cellular proliferation, gene rearrangements, selection, and differentiation, and it provides a powerful model to study DNA repair processes in vivo. Analysis of the contribution of the base excision repair pathway in lymphocyte development has been lacking primarily owing to the essential nature of this repair pathway. However, mice deficient for the base excision repair enzyme, apurinic/apyrimidinic endonuclease 2 (APE2) protein develop relatively normally, but they display defects in lymphopoiesis. In this study, we present an extensive analysis of bone marrow hematopoiesis in mice nullizygous for APE2 and find an inhibition of the pro-B to pre-B cell transition. We find that APE2 is not required for V(D)J recombination and that the turnover rate of APE2-deficient progenitor B cells is nearly normal. However, the production rate of pro- and pre-B cells is reduced due to a p53-dependent DNA damage response. FACS-purified progenitors from APE2-deficient mice differentiate normally in response to IL-7 in in vitro stromal cell cocultures, but pro-B cells show defective expansion. Interestingly, APE2-deficient mice show a delay in recovery of B lymphocyte progenitors following bone marrow depletion by 5-fluorouracil, with the pro-B and pre-B cell pools still markedly decreased 2 wk after a single treatment. Our data demonstrate that APE2 has an important role in providing protection from DNA damage during lymphoid development, which is independent from its ubiquitous and essential homolog APE1.

Original languageEnglish
Pages (from-to)1943-1950
Number of pages8
JournalJournal of Immunology
Volume186
Issue number4
DOIs
Publication statusPublished - Feb 15 2011

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DNA-(Apurinic or Apyrimidinic Site) Lyase
B-Lymphoid Precursor Cells
Endonucleases
B-Lymphocytes
DNA Repair
DNA Damage
Bone Marrow
V(D)J Recombination
Lymphopoiesis
Interleukin-7
Gene Rearrangement
Hematopoiesis
Stromal Cells
Coculture Techniques
Fluorouracil
Cell Proliferation
Lymphocytes
Enzymes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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Apurinic/apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge. / Guikema, Jeroen E.J.; Gerstein, Rachel M.; Linehan, Erin K.; Cloherty, Erin K.; Evan-Browning, Eric; Tsuchimoto, Daisuke; Nakabeppu, Yusaku; Schrader, Carol E.

In: Journal of Immunology, Vol. 186, No. 4, 15.02.2011, p. 1943-1950.

Research output: Contribution to journalArticle

Guikema, Jeroen E.J. ; Gerstein, Rachel M. ; Linehan, Erin K. ; Cloherty, Erin K. ; Evan-Browning, Eric ; Tsuchimoto, Daisuke ; Nakabeppu, Yusaku ; Schrader, Carol E. / Apurinic/apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge. In: Journal of Immunology. 2011 ; Vol. 186, No. 4. pp. 1943-1950.
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