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 6

Abnormal myelopoiesis develops in Fancc–/– mice after multiple cycles of Alum injection.

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Abnormal myelopoiesis develops in Fancc–/– mice after multiple cycles of...
(A) Survival of Fancc–/– mice is low during multiple cycles of Alum injection. Fancc–/–, Fancc+/–, and WT mice were injected with Alum or saline every 4 weeks. The percentage of mice surviving during the treatment period was determined. All mice in the saline group survived during the treatment period. Curves for WT and Fancc–/– mice were significantly (P < 0.01) different by log-rank analysis. (B) Immature myeloid cells appear in the circulation of Fancc–/– mice after multiple Alum injections. Peripheral blood from the mice above was analyzed every 4 weeks for immature circulating myeloid cells (blasts). Statistically significant difference in myeloid blasts over time in Alum-injected mice is indicated by *P < 0.01 and with versus without Alum injection by **P < 0.01. No myeloid blasts were observed in WT or Fancc+/– mice during treatment. (C) Photomicrograph of immature myeloid cells in the circulation of Fancc–/– mice. Peripheral blood from a Fancc–/– mouse after 2 Alum injection cycles was analyzed microscopically (original magnification, ×40). Myeloid blasts are indicated by arrows, and a lymphocyte is indicated by an asterisk.