A Systematic Review of the Role of Runt-Related Transcription Factor 1 (RUNX1) in the Pathogenesis of Hematological Malignancies in Patients With Inherited Bone Marrow Failure Syndromes.

Somatic () mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Mono-allelic mutations in germline cells may cause familial platelet disorder (FPD), an inherited bone marrow failure syndrome (IBMFS) associated with an increased lifetime risk of AML. It is suspected that additional mutations may play a role in the pathogenesis of hematological malignancies in IBMFS. This review aims to study the role of mutations in the pathogenesis of hematological malignancies in patients with IBMFS. A PubMed database search was conducted using the following medical subject heading (MeSH) terms: "inherited bone marrow failure syndromes," "hematological neoplasms," "gene expression regulation, leukemic," "RUNX1 protein, human," "RUNX1 protein, mouse," and "Neutropenia, Severe Congenital, Autosomal recessive." Three studies published in 2020 were identified as meeting our inclusion and exclusion criteria. Leukemic progression in severe congenital neutropenia was used as a disease model to evaluate the clinical, molecular, and mechanistic basis of mutations identified in hematological malignancies. Studies in mice and genetically reprogrammed or induced pluripotent stem cells (iPSCs) have shown that isolated mutations are weakly leukemogenic and only initiate hyperproduction of immature hematopoietic cells when in combination with () mutations. Despite this, whole-exome sequencing (WES) performed on leukemogenic transformed cells revealed that all AML cells had an additional mutation in the  () gene that caused hyperproduction of the ten-eleven translocation (TET2) protein. This protein causes inflammation in cells with mutations. This process is thought to be critical for clonal myeloid malignant transformation (CMMT) of leukemogenic cells. In conclusion, the combinations of and mutations have a prominent effect on myeloid differentiation resulting in the hyperproduction of myeloblasts. In other studies, it has been noted that the mutations in and genes are not sufficient for the full transformation of leukemogenic cells to AML, and an additional clonal mutation in the gene is essential for full transformation to occur. These data have implicitly demonstrated that mutations are critical in the pathogenesis of various hematological malignancies, and further investigations into the role of are paramount for the development of new cancer treatments.