Increased Fanconi C expression contributes to the emergency granulopoiesis response
Liping Hu, … , Elizabeth Hjort, Elizabeth A. Eklund
Liping Hu, … , Elizabeth Hjort, Elizabeth A. Eklund
Published August 8, 2013
Citation Information: J Clin Invest. 2013;123(9):3952-3966. https://doi.org/10.1172/JCI69032.
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Research Article Hematology

Increased Fanconi C expression contributes to the emergency granulopoiesis response

Abstract

Emergency granulopoiesis is a component of the innate immune response that is induced in response to infectious or inflammatory challenge. It is characterized by the rapid expansion and differentiation of granulocyte/monocyte progenitor (GMP) populations, which is due in part to a shortened S-phase of the cell cycle. We found that IRF8 (also known as ICSBP), an interferon regulatory transcription factor that activates phagocyte effector genes during the innate immune response, activates the gene encoding Fanconi C (Fancc) in murine myeloid progenitor cells. Moreover, IRF8-induced Fancc transcription was augmented by treatment with IL-1β, an essential cytokine for emergency granulopoiesis. The Fanconi pathway participates in repair of stalled or collapsed replication forks during DNA replication, leading us to hypothesize that the Fanconi pathway contributes to genomic stability during emergency granulopoiesis. In support of this hypothesis, Fancc–/– mice developed anemia and neutropenia during repeated, failed episodes of emergency granulopoiesis. Failed emergency granulopoiesis in Fancc–/– mice was associated with excess apoptosis of HSCs and progenitor cells in the bone marrow and impaired HSC function. These studies have implications for understanding the pathogenesis of bone marrow failure in Fanconi anemia and suggest possible therapeutic approaches.

Authors

Liping Hu, Weiqi Huang, Elizabeth Hjort, Elizabeth A. Eklund

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Figure 4

FANCC reexpression rescues DNA repair in IRF8-deficient cells.

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FANCC reexpression rescues DNA repair in IRF8-deficient cells. (A) IRF8 ...
(A) IRF8 knockdown decreases repair of MMC-damaged plasmid in U937 transfectants, and this is reversed by FANCC and/or FANCF expression. U937 cells were stably transfected with a vector to express an IRF8-specific shRNA or scrambled control shRNA. These cells were cotransfected with a reporter plasmid and a vector to express FANCC, FANCF, FANCC plus FANCF, or empty vector control. Some reporter plasmids were pretreated with MMC to generate DNA crosslinks. Reporter activity was determined in RA/DMF-differentiated transfectants. Statistically significant difference in reporter expression with versus without IRF8 knockdown is indicated by *P < 0.01 and in IRF8-knockdown cells with versus without reexpression of FANCC, FANCF, or both by **P < 0.01 or ***P < 0.01. Statistically significant differences with IRF8 knockdown and reexpression of FANCC or FANCF versus reexpression of both are indicated by #P < 0.01 or ##P < 0.01. (B) Expression of Fancc is decreased in U937 stable transfectants with IRF8 knockdown. U937 stable transfections from the experiments above were analyzed for expression of Irf8 and Fancc mRNA by real-time PCR. Statistically significant differences with versus without IRF8 knockdown are indicated by *P < 0.01 and **P < 0.01.