Fanconi anemia (FA) is an uncommon, autosomal recessive, multisystem disorder characterized by near uniform loss of bone marrow function by late adolescence. Much has been learned about the activity of the 16 Fanconi genes whose coordinate function guides DNA double-strand break repair that prevents accrual of DNA damage, thereby protecting cells from malignant transformation and clonal evolution. Met with initial skepticism when first proposed, the FA pathway has gained credence (and expanded to a state of dizzying complexity) over the past decade and now serves as a roadmap for understanding the molecular and cellular basis of the disease. However, the discovery of the overlap of some genes of the FA pathway with some genes of the BRCA pathway (i.e., the pathway that is defective in patients with inherited forms of breast and ovarian cancers and now called the FA/BRCA pathway) skewed FA research in the direction of identifying and characterizing the mechanisms that underlie neoplastic transformation and away from investigation both of the basis of the vulnerability that erodes the stem cell pool and of the physiologic function of FA proteins in stem cell self renewal. But now a study from the laboratory of Elizabeth Eklund at the Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, provides a new perspective on the basis of bone marrow failure in FA.
The studies of Liping Hu and colleagues focused on a connection between emergency granulopoiesis, a component of the innate immune response, and hematopoietic failure in a murine model of FA. Emergency granulopoiesis is induced in response to an infectious or inflammatory challenge and is characterized by rapid expansion and differentiation of granulocyte/monocyte progenitor populations, a process that is due in part to a shortened S-phase of the cell cycle. Based on experiments that showed that transcription of the FA gene Fancc is augmented by interleukin Iβ (IL-1β), an essential emergency granulopoiesis cytokine, the authors hypothesized that the FA/BRCA pathway contributes to genomic stability during emergency granulopoiesis. The authors challenged their hypothesis by inducing emergency granulopoiesis in wild-type and Fancc-deficient mice using the vaccine adjuvant alum. Those experiments showed failed emergency granulopoiesis in Fancc-deficient mice, and with repeated successive rounds of challenge with the inflammatory stimulant, the knockout animals experienced progressive anemia and neutropenia. The peripheral blood cytopenias were found to coincide with apoptotic loss of hematopoietic stem cells and myeloid progenitors in the bone marrow. The effect was mediated by G-CSF and by IL-1β augmentation of the interferon regulatory transcription factor IRF8, which initiates transcription of Fancc, and ameliorated by blockade of the interleukin receptor-1 (IL-1R). The results elucidated the mechanistic underpinnings of prior work that showed that FA stem cells were abnormally susceptible to interferon-γ and may explain the relatively poor response to G-CSF mobilization observed in Fancc mice and in some FA patients. The experimental findings also appear to validate the long-held notion that “protective” animal husbandry in an infection-free environment may inadvertently account for the lack of spontaneous post-natal hematopoietic failure that plagues many murine FA models.
The novel findings of Hu and colleagues bring to mind Einstein’s view that “it is the theory which decides what we can observe,” as these and other studies suggest multiple functions for individual FA proteins, with activity outside the canonical repair of interstrand crosslinks or cytokine defense. In the current study, IL-1β and G-CSF transcriptionally upregulated Fancc and Fancf, but did not consistently alter Fancd2 levels. The DNA pathway function of FA proteins may continue to be instructive for understanding alkylating agent detoxification, but not necessarily for understanding stem cell self-renewal. Involvement in aldehyde detoxification, recently shown by others, and innate immune defense, shown here, serve to reinvigorate, and redirect, our approach to understanding hematopoietic failure and the physiologic role of FA proteins.
In Brief
Other research models of acquired bone marrow failure support the role of innate immunity in regulating the hematopoietic stem cell pool.1 The article by Hu and colleagues now extends those observations in an unexpected way to FA. The findings need to be validated, but they suggest that stem cells from individuals with FA (and perhaps FA carriers) are vulnerable to recurrent infectious stimuli. The work raises additional questions including the following: Does innate immunity trigger DNA damage? How does emergency granulopoiesis relate to stem cell function at a mechanistic level? Notably, the paper suggests a novel therapeutic strategy that may yet preempt the loss of bone marrow stem cells in children with FA.
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Competing Interests
Dr. Kurre indicated no relevant conflicts of interest.
