title: Deletion of Irf5 protects hematopoietic stem cells from DNA damage-induced apoptosis and suppresses γ-irradiation-induced thymic lymphomagenesis.
abstract: Repeated low-dose γ-irradiation (IR) induces thymic lymphoma in mice because of oncogenic mutations propagating from a primitive hematopoietic stem/progenitor cell (HSC) in the bone marrow. It is well known that IR-induced thymic lymphomagenesis is markedly enhanced by p53 deficiency, yet data also indicate that p53-dependent apoptosis can actively drive tumor formation in this model. The latter was recently expounded on by findings from Puma-deficient mice, indicating that loss of this proapoptotic p53 target gene results in protection from IR-induced lymphomagenesis rather than enhanced susceptibility to. Similar to Puma, the transcription factor interferon regulatory factor 5 (Irf5) has been reported as a p53 target gene and is required for DNA damage-induced apoptosis. To date, no studies have been performed to elucidate the in vivo role of IRF5 in tumorigenesis. Given its essential role in DNA damage-induced apoptosis, we explored the tumor suppressor function of IRF5 in IR-induced thymic lymphomagenesis. Somewhat surprisingly, we found that thymic lymphoma development was significantly suppressed in Irf5(-/-) mice as compared with wild-type littermates. Suppression was due, in part, to reduced thymocyte and HSC apoptosis, resulting in reduced compensatory proliferation, and reduced replication stress-associated DNA damage. The observed effects were independent of p53 or Puma as these proteins were upregulated in Irf5(-/-) mice in response to IR. This study demonstrates an important new role for IRF5 in maintaining HSC homeostasis after IR and supports the non-redundant functions of IRF5, p53 and PUMA in DNA damage-induced lymphomagenesis. We propose that IRF5 may be an attractive target for developing therapeutic agents to ameliorate radiation-induced bone marrow injury.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA [2] New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: X
authors.initials: X
authors.lastname: Bi
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA [2] New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: D
authors.initials: D
authors.lastname: Feng
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA [2] New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Korczeniewska
authors.affiliation: New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: N
authors.initials: N
authors.lastname: Alper
authors.affiliation: New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hu
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA [2] New Jersey Medical School-University Hospital Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Barnes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D004249:DNA Damage; D005720:Gamma Rays / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology* / Q000528:radiation effects; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D060168:Thymocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D013953:Thymus Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins