Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging

Abstract

Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features.

Keywords: Aging; Bone marrow failure; DNA repair; Epigenetic; Fanconi Anemia; Hematopoietic stem cells; Inflammatory response; Oxidative stress; Telomere.

Figure 1. Clinical symptoms and cellular phenotypes of FA symptomatic of accelerated aging

FA patients face many health issues in their childhood (teens) and early adulthood (twenties) that also challenge healthy individuals as they age into their fifties and sixties. These include but are not limited to: a dysfunctional bone marrow leading to anemia and immunodeficiency, chronic inflammation, as wells as squamous cell carcinomas and acute myeloid leukemia. Another set of clinical features shared by aging individuals and FA patients are: a decline in endocrine functions, sarcopenia and osteopenia.

Figure 2. Dual problems in DNA transactions and inflammatory response are responsible for hematopoietic stem cell defects and bone marrow failure in FA

Reactive aldehydes and ROS generated during cellular metabolism and as a consequence of an inflammatory response will induce DNA damage, triggering the DNA damage response (DDR). This will halt cell cycle progression and trigger repair pathways that will attempt to repair the damage. A persistent DDR will eventually lead to either apoptosis or senescence. Senescent cells are characterized by the senescence associated secretory phenotype (SASP) that will induce inflammatory responses in neighboring cells. In FA cells, the inflammation/senescence cycle is fueled at several levels: (a) deficient oxidative stress signaling induces a pro-oxidant state, (b) inefficient repair results in a persistent DDR, and (c) an increase in the transcription of NF-κB induces the SASP, generating more inflammation (d) and perpetuating the vicious cycle.