Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Abstract

Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.

DNA methylation analysis using RUNX1-mutated cells reveals association of FLI1 to familial platelet disorder with associated myeloid malignancies caused by a mutation in the transactivation domain of RUNX1

“…Recently, next generation sequencing-based studies reported FLI1 mutations that disrupt its DNA-binding ability as a cause of FPD [56], supporting our ndings. Although ELF1 was excluded from this study because of its lack of interference with DNA demethylation [19], it has been reported as a FLI1 target gene [57]. Indeed, the expression patterns of ELF1 and FLI1 were correlated in AML cells [58], whereas no evidence to date suggests that ELF1 is crucial for megakaryopoiesis.…”

“…The reason for the downregulation of the expression of FLI1 in HPCs by a RUNX1 TAD mutation remains unclear. FLI1 is also known to regulate the expression of RUNX1 [57,59]. However, no studies to date have indicated that RUNX1 directly regulates the expression of FLI1.…”

FLI1 is associated with regulation of DNA methylation and megakaryocytic differentiation in FPDMM caused by a RUNX1 transactivation domain mutation

“…Recently, next generation sequencing-based studies reported FLI1 mutations that disrupt its DNA-binding ability as a cause of FPD 43 , supporting our findings. Although ELF1 was excluded from this study because of its lack of interference with DNA demethylation 20 , it has been reported as a FLI1 target gene 44 . Indeed, the expression patterns of ELF1 and FLI1 were correlated in AML cells 45 , whereas no evidence to date suggests that ELF1 is crucial for megakaryopoiesis.…”

“…The reason for the downregulation of the expression of FLI1 in HPCs by a RUNX1 TAD mutation remains unclear. FLI1 is also known to regulate the expression of RUNX1 44 , 46 . However, no studies to date have indicated that RUNX1 directly regulates the expression of FLI1.…”