The Role of Innate Immune Dysfunction in Inherited Bone Marrow Failure
Authors: Bagby Grover C. 
Published: October 2019

The 16 Fanconi anemia (FA) genes encode proteins that facilitate cellular responses to DNA damage. A nuclear complex of eight of these proteins facilitates the monoubiquitination of FANCD2 and FANCI and permits the proper orchestration of DNA crosslink repair. Loss of any one of these “core complex” proteins disrupts repair. While the resulting genetic instability phenotype is broadly shared across tissues and cell types, the clinical phenotype involves a more narrow set of organ systems. Bone marrow failure (BMF) is nearly universal and progresses at a currently unpredictable pace in individual patients. The relative risk for clonal evolution to myelodysplasia (MDS) and acute myeloid leukemia (AML) is also high. Exposure to both exogenous (in human and knockout mouse models) and endogenous (knockout mouse) crosslinking agents rapidly results in fatal aplastic anemia, so there is a general tendency for those in the field to attribute FA BMF simply to DNA damage caused by endogenous crosslinking agents such as aldehydes. However, currently there exists no formal biochemical evidence that stem cells suffering from exposure to endogenous aldehydes fail to survive solely as a consequence of DNA damage inflicted upon them by aldehydes per se. Moreover, FA proteins are known to interact with mitochondrial and cytoplasmic proteins that modulate responses to inflammation and oxidative stress. We and others have tested and confirmed the hypothesis that inflammatory cytokines contribute to hematopoietic suppression in FA. For example, FANCC and FANCA progenitor cells are hypersensitive to the suppressive effects of IFNγ, Mip1α, TNF, TGFβ, and IL-1. Moreover, FANCC- and FANCA-deficient macrophages exposed to specific toll-like receptor agonists (TLR7/8) overproduce precisely the same cytokines to which FA HSC are intolerant. Critically important in vivo studies have shown that repeated activation of the inflammatory response in FA-deficient mice using lps, TNF, or antigen/adjuvant exposure results in stem cell exhaustion, a phenomenon that can be reliably modeled in vitro with cultured multipotential hematopoietic stem and progenitor (Kit+Sca+Lin- [LSK]) cells. Two potential explanations for FA stem cell exhaustion have been proposed. The first is that the inflammatory process induces “replicative stress,” followed by replication fork collapse, DNA damage and stem cell death. The second is that FA proteins are multifunctional and that the core complex proteins have evolved to independently: (1) promote self-replication and cytokine resistance of hematopoietic stem and progenitor cells; and (2) restrain production of inflammatory cytokines by macrophages. Experimental evidence reconciling both views will be reviewed including recent studies demonstrating that the TLR response in FA macrophages is dependent upon p38 MAPK activation, enhanced by endogenous aldehydes, and independent of macrophage DNA damage. These models have informed our concepts of clonal evolution in FA as well and have demonstrated that stem cell exhaustion is a selective force that favors evolution of neoplastic clones. Pang’s group, for example, has shown that when FA LSK cells are exposed to both survival factors and TNF ex-vivo, TNF-resistant preleukemic stem cells can be selected.1When transplanted into sub-lethally radiated mice, these selected TNF-resistant cells lead to the evolution of overt AML. These findings indicate that a somatic mutation or epigenetic change in a single stem cell that results in cytokine resistance has a high likelihood of selective expansion. Consequently, interdicting the hyperactive innate immune response may not only enhance stem cell survival in FA, but might forestall clonal evolution as well.
Reference: Li J, Sejas DP, Zhang X et al. TNF-alpha induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. J.Clin.Invest. 2007;117:3283-3295.

Disclosures
No relevant conflicts of interest to declare.