RUNX1 Mutations in Inherited and Sporadic Leukemia.

Dana C Bellissimo,Nancy A Speck

doi:10.3389/fcell.2017.00111

Abstract

RUNX1 is a recurrently mutated gene in sporadic myelodysplastic syndrome and leukemia. Inherited mutations in RUNX1 cause familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). In sporadic AML, mutations in RUNX1 are usually secondary events, whereas in FPD/AML they are initiating events. Here we will describe mutations in RUNX1 in sporadic AML and in FPD/AML, discuss the mechanisms by which inherited mutations in RUNX1 could elevate the risk of AML in FPD/AML individuals, and speculate on why mutations in RUNX1 are rarely, if ever, the first event in sporadic AML.

Highlights

Acute leukemia is caused by the acquisition of mutations in hematopoietic stem and/or progenitor cells (HSPCs) that promote their clonal expansion and impair downstream differentiation
It was originally thought that inherited RUNX1 mutations cause leukemia predisposition because every hematopoietic stem cell (HSC) in an FPD/acute myeloid leukemia (AML) individual is already one mutation along the path to AML
We envision a model whereby RUNX1 mutations increase the rate at which secondary mutations are acquired; increased inflammatory signals delivered by RUNX1 mutant myeloid lineage cells or other cells in the RUNX1 mutant bone marrow microenvironment provide a selective pressure that confers a competitive advantage to FPD/AML HSCs that have acquired secondary mutations (Figure 1)

Summary

INTRODUCTION

Acute leukemia is caused by the acquisition of mutations in hematopoietic stem and/or progenitor cells (HSPCs) that promote their clonal expansion and impair downstream differentiation. Disease progression is caused by the acquisition of secondary mutations in HSCs containing initiating mutations These secondary, driver mutations involve genes encoding several functional categories of proteins including transcription factors (e.g., CEBPA, RUNX1, GATA2, and ETV6), signaling molecules (FLT3, NRAS, PTPN11, KRAS, KIT, CBL, and NF1), splicing factors (SRSF2, SF3B1, and U2AF1), and proteins with other functions (NPM1, SMC1A) (Cancer Genome Atlas Research Network et al, 2013; Papaemmanuil et al, 2016). Mono- and biallelic mutations in RUNX1 include deletions, missense, splicing, frameshift, and nonsense mutations These mutations are mechanistically distinct from the chromosomal translocations and confer a worse prognosis

Multiple No

DEFECTS IN DNA REPAIR PATHWAYS IN

SELECTION OF HSCs WITH SECONDARY

CONCLUSIONS