NK Cell Development and Function in Patients with Fanconi Anemia

Abstract

Fanconi anemia (FA) is an inherited disorder characterized by diverse congenital malformations, progressive pancytopenia, and predisposition to hematological malignancies and solid tumors. The role of the Fanconi anemia pathway in DNA repair mechanisms and genome instability is well studied. However, the consequences of inherited mutations in genes encoding the FA proteins and the acquired mutations due to impaired DNA repair complex in immune cells are far from understood. Patients with FA show bone marrow failure (BMF) and have a higher risk of developing myelodysplasia (MDS) or acute myeloid leukemia (AML) which are directly related to having chromosomal instability in hematopoietic stem cells and their subsequent progeny. However, immune dysregulation can also be seen in FA. As mature descendants of the common lymphoid progenitor line, NK cells taken from FA patients are dysfunctional in both NK cell-mediated cytotoxicity and cytokine production. The molecular bases for these defects are yet to be determined. However, recent studies have provided directions to define the cause and effect of inherited and acquired mutations in FA patients. Here, we summarize the recent studies in the hematopoietic dysfunction, focusing on the impairment in the development and functions of NK cells in FA patients, and discuss the possible mechanisms and future directions.

FIG. 1:

Fanconi anemia pathway and DNA repair. ICLs are covalent binding of two nucleotides in DNA strands caused by exogenous and endogenous factors that can impede DNA replication and transcription in cells. The illustration depicts the pathway and the core complex associated with the Fanconi anemia repair pathway.

FIG. 2:

Potential mechanisms associated with impaired NK cell development and function in Fanconi anemia patients. Fanconi anemia subtype-G mutation as a model to illustrate the primary mutation in Fanconi anemia genes and the acquired second-hit mutations in NK cells. The second-hit mutations can lead to developmental and functional defects.