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 9

Hematopoietic recovery is delayed in mice transplanted with SCA1+ cells from Alum-treated Fancc–/– mice versus control Fancc–/– mice.

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Hematopoietic recovery is delayed in mice transplanted with SCA1+ cells ...
(A) Circulating neutrophils increase more slowly in mice transplanted with SCA1+ bone marrow cells from Alum-treated versus control Fancc–/– mice. Fancc–/– mice were injected with Alum or saline, and bone marrow was harvested 2 weeks later. LIN–SCA1+ cells were transplanted into lethally irradiated WT mice, and peripheral neutrophil counts were determined each week. Statistically significant differences with transplant from Alum- versus saline-treated donors is indicated by *P < 0.01 or **P < 0.01. (B) Hgb concentration increases more slowly in mice transplanted with SCA1+ bone marrow cells from Alum-treated versus control Fancc–/– mice. Hgb concentrations were determined for the mice above. Statistically significant differences with transplant from Alum- versus saline-injected donors are indicated by *P < 0.01 or **P < 0.01. (C) Platelet counts increase more slowly in mice transplanted with SCA1+ bone marrow cells from Alum-treated versus control Fancc–/– mice. Platelet counts were determined for the mice above. Statistically significant differences with transplant from Alum- versus saline-injected donors are indicated by *P < 0.01 or **P < 0.01.