Normal and transforming functions of RUNX1: A perspective

Abstract

Converging studies from many investigators indicate that RUNX1 has a critical role in the correct maintenance of essential cellular functions during embryonic development and after birth. The discovery that this gene is also frequently mutated in human leukemia has increased the interest in the role that RUNX1 plays in both normal and transforming pathways. Here, we provide an overview of the many roles of RUNX1 in hematopoietic self-renewal and differentiation and summarize the information that is currently available on the many mechanisms of RUNX1 deregulation in human leukemia.

Novel RUNX1 mutations in familial platelet disorder with enhanced risk for acute myeloid leukemia: clues for improved identification of the FPD/AML syndrome

“…The mutant transcript results in an in-frame deletion of 35 amino acids that disrupts part of the Runt homology domain and domains reported to bind the coactivators p300/CBP and corepressor Sin3A. 4 Owing to its limited resolution and the small size of the deletion, this aberration was not detected by whole genome SNP array on DNA derived from bone marrow of the proband, which did show a trisomy of chromosome 21. This trisomy has targeted the mutant allele as the deletion in the index patient was detected in two of the three copies of chromosome 21 (Figure 2b).…”

Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions

“…AML1 has been reported to have a dual role in promoting cell cycle progression and differentiation, which may be dependent on the presence of different factors that are present (Mikhail et al, 2006). In T29 cells, we observed that AML1b inhibits the growth of these cells mediated possibly through upregulation Splice variant of AML1b confers loss of wild-type functions M Nanjundan et al of p21 levels, and further, inhibits the migratory potential of these cells.…”

“…Acute myeloid leukemia (AML) 1 belongs to a small family of transcriptional regulators whose members contain a DNA-binding runt homology domain (RHD) which have distinct tissue-specific expression and function (Mikhail et al, 2006). AML1 encodes the a-subunit of the transcription factor PEBP2/CBFb involved in the recognition of general transcription coregulators.…”

“…AML1 exhibits a complex pattern of tissue-regulated expression at the level of transcription, splicing and translation (Levanon et al, 1996). Thus far, there are four AML1-identified alternative splice isoforms, namely AML1a, AML1b, AML1 Del N and AML1c, all of which contain an RHD (Miyoshi et al, 1995;Zhang et al, 1997;Mikhail et al, 2006). AML1b is reported to be the most abundant isoform and exhibits the ability to transform NIH 3T3 cells (Yamaguchi et al, 2004).…”

“…AML1b is reported to be the most abundant isoform and exhibits the ability to transform NIH 3T3 cells (Yamaguchi et al, 2004). Interestingly, AML1 undergoes several post-translational modifications including acetylation, methylation and ubiquitination leading to proteosome-mediated degradation (Mikhail et al, 2006). Although AML1, located at 21q22.12, can be amplified at the DNA level (Berger, 1997;Kirschnerova et al, 2006), overexpression of the AML1 transcripts may also occur in the absence of gene amplification of the AML1 locus suggesting that deregulation of the AML1 promoter is an alternative mechanism of increased AML1 levels.…”