The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis

Abstract

Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond–Blackfan anemia, Shwachman–Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency and SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated their classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond–Blackfan anemia), ribosome assembly (Shwachman–Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita). The pathogenetic mechanisms of IBMFSs remain to be characterized fully, but an overarching hypothesis states that different stresses elicit TP53-dependent growth arrest and apoptosis of hematopoietic stem, progenitor, and precursor cells. Here, we review the IBMFSs and propose a role for pro-inflammatory cytokines, such as TGF-β, IL-1β, and IFN-α, in mediating the cytopenias. We suggest a pathogenic role for cytokines in the transformation to myeloid neoplasia and hypothesize a role for anti-inflammatory therapies.

Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management

“…In addition, FA cells are hypersensitive to endogenous and exogenous stresses, leading to the unrestricted activation of the DNA damage response (hyperactive ATM/TP53/p21 pathway, ATR/CHK1 pathway, p16/RB, NF-κB, and p38) and cell cycle arrest. Thereby, oxidative stress leads to progressive TP53-dependent depletion of the hematopoietic stem and progenitor cell (HSPC) pool, ultimately leading to bone marrow failure [39]. Hematological symptoms usually start with thrombocytopenia and leukopenia and can progress towards pancytopenia [40].…”