New Insights into the Fanconi Anemia Pathogenesis: A Crosstalk Between Inflammation and Oxidative Stress

Abstract

Fanconi anemia (FA) represents a rare hereditary disease; it develops due to germline pathogenic variants in any of the 22 currently discovered FANC genes, which interact with the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway to maintain genome integrity. FA is characterized by a triad of clinical traits, including congenital anomalies, bone marrow failure (BMF) and multiple cancer susceptibility. Due to the complex genetic background and a broad spectrum of FA clinical symptoms, the diagnostic process is complex and requires the use of classical cytogenetic, molecular cytogenetics and strictly molecular methods. Recent findings indicate the interplay of inflammation, oxidative stress, disrupted mitochondrial metabolism, and impaired intracellular signaling in the FA pathogenesis. Additionally, a shift in the balance towards overproduction of proinflammatory cytokines and prooxidant components in FA is associated with advanced myelosuppression and ultimately BMF. Although the mechanism of BMF is very complex and needs further clarification, it appears that mutual interaction between proinflammatory cytokines and redox imbalance causes pancytopenia. In this review, we summarize the available literature regarding the clinical phenotype, genetic background, and diagnostic procedures of FA. We also highlight the current understanding of disrupted autophagy process, proinflammatory state, impaired signaling pathways and oxidative genotoxic stress in FA pathogenesis.

Keywords: Fanconi anemia; autophagy; bone marrow failure; cancers; inflammatory process; oxidative stress.

Figure 4

Schematic representation of how biallelic pathogenic variants in FANC (Fanc^−/−) genes trigger a vicious circle between proinflammatory cytokines, oxidative genotoxic stress and MAPK, Notch as well as NF-κB signaling pathways.

Figure 1

Schematic concept of Fanconi anemia pathogenesis.

Figure 2

A simplified diagnostic algorithm for Fanconi anemia, including indications for FA diagnosis and general genetic tests.

Figure 3

Chromosomal aberrations after addition of cross-linking agent (MMC) to the lymphocyte culture of patient with FA (A) and healthy control (B). Arrows indicate chromatid breaks.