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.
View: Text | PDF
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

×

Figure 8

Alum injection induces apoptosis in the bone marrow of FANCC-deficient mice.

Options: View larger image (or click on image) Download as PowerPoint
Alum injection induces apoptosis in the bone marrow of FANCC-deficient m...
(A) Alum injection increases apoptosis in the bone marrow of FANCC-deficient, but not WT, mice. TUNEL assays were performed on sternal bone marrow from WT and Fancc–/– mice 2 weeks after i.p. injection with Alum or saline. Positive cells were counted per high-power field (hpf). Statistically significant differences in cell numbers in WT versus Fancc–/– bone marrow are indicated by *P < 0.01. (B) Bone marrow from FANCC-deficient mice has increased apoptosis by TUNEL assay. Photomicrographs (original magnification, ×40) were obtained from the sternal bone marrow samples, described above. (C) Hematopoietic stem and myeloid progenitor cells are apoptotic in the bone marrow of Alum-injected Fancc–/– mice. Bone marrow from WT or Fancc–/– mice was harvested 2 weeks after injection with Alum or saline and analyzed by flow cytometry to identify the percentage of Annexin V–positive cells in the SCA1+, CD34+, or GR1+ populations. Statistically significant differences in the percentages of Annexin V–positive cells in WT versus Fancc–/– bone marrow populations are indicated by *P < 0.01, **P < 0.01, or ***P < 0.01.