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 2

IRF8 activates a cis element in the proximal Fancc promoter.

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IRF8 activates a cis element in the proximal Fancc promoter. (A) The F...
(A) The Fancc 5′ flank has conserved consensus sequences for interferon regulatory factor binding. The human (black) and murine (blue) Fancc 5′ flanks were compared for conserved consensus sequences for interferon regulatory factor binding. The identified sequences are indicated in red. Every 50 bp, counting from the transcription start site, are indicated by a black circle. (B) IRF8 activates the Fancc promoter. U937 myeloid cells were cotransfected with reporter constructs containing truncations of the Fancc 5′ flank and a vector to express IRF8 (or control vector). Reporter gene activity was determined with or without RA/DMF treatment. Reporter gene activity that is not significantly different within groups is indicated by a or b. Statistically significant differences with versus without IRF8 overexpression are indicated by *P < 0.01 and **P < 0.01. (C) IRF8 activates a cis element found between –56 and –48 bp of the Fancc promoter. U937 cells were cotransfected with a reporter construct with 3 copies of the –58- to –46-bp sequence of the Fancc promoter linked to a minimal promoter and a vector to express IRF8 (or relevant control vectors). Reporter gene activity was determined with or without RA/DMF. Statistically significant differences with versus without IRF8 overexpression are indicated by *P < 0.01 or ***P < 0.01 and with versus without differentiation by **P < 0.01.