Proleukemic RUNX1 and CBFβ Mutations in the Pathogenesis of Acute Leukemia

Abstract

The existence of non-random mutations in critical regulators of cell growth and differentiation is a recurring theme in cancer pathogenesis and provides the basis for our modern, molecular approach to the study and treatment of malignant diseases. Nowhere is this more true than in the study of leukemogenesis, where research has converged upon a critical group of genes involved in hematopoietic stem and progenitor cell self-renewal and fate specification. Prominent among these is the heterodimeric transcriptional regulator, RUNX1/CBFbeta. RUNX1 is a site-specific DNA-binding protein whose consensus response element is found in the promoters of many hematopoietically relevant genes. CBFbeta interacts with RUNX1, stabilizing its interaction with DNA to promote the actions of RUNX1/CBFbeta in transcriptional control. Both the RUNX1 and the CBFbeta genes participate in proleukemic chromosomal alterations. Together they contribute to approximately one-third of acute myelogenous leukemia (AML) and one-quarter of acute lymphoblastic leukemia (ALL) cases, making RUNX1 and CBFbeta the most frequently affected genes known in the pathogenesis of acute leukemia. Investigating the mechanisms by which RUNX1, CBFbeta, and their proleukemic fusion proteins influence leukemogenesis has contributed greatly to our understanding of both normal and malignant hematopoiesis. Here we present an overview of the structural features of RUNX1/CBFbeta and their derivatives, their roles in transcriptional control, and their contributions to normal and malignant hematopoiesis.

Emergence of heterogeneity in acute leukemias

“…There is evidence that many of them lead to increased self-renewal. Important examples for genes where mutations lead to increased self-renewal are the chromatin modifiers TET2 [ 53 ], DNMT3A [ 54 ] and MLL [ 55 ] or the transcription factors C/EBP α [ 56 ], RUNX1/CBF β [ 57 , 58 ] and factors encoded by the HOX genes, e.g., as NUP98-HOXA9 [ 59 ]. Other examples include the isocitrate dehydrogenase IDH1 [ 60 ], the NRAS gene [ 61 ] or the multi-functional protein NPM1 [ 62 ].…”

RUNX1: A MicroRNA Hub in Normal and Malignant Hematopoiesis

“…RUNX1 is one of the most common targets of chromosomal translocations in acute leukemia [40]. Over 50 chromosome translocations affecting the RUNX1 gene on chromosome 21 and over 20 different partner genes have been described [40,77,78]. One of the most recurrent translocations involving RUNX1 is the t(8;21), which is found in 30%–40% of acute myeloid leukemia (AML) FAB-M2 [40,77].…”

RUNX Proteins as Epigenetic Modulators in Cancer

“…RUNX1 is a key regulator of hematopoietic cell development [ 3 , 47 , 48 ]. During mouse embryonic development, RUNX1 is essential for the generation of hematopoietic stem cells, and the deletion of Runx1 blocks the hematopoiesis process.…”