Truncated RUNX1 protein generated by a novel t(1;21)(p32;q22) chromosomal translocation impairs the proliferation and differentiation of human hematopoietic progenitors

• Published in: Oncogene 2016-01, Vol.35 (1), p.125-134
• Main Authors: Rodriguez-Perales, S, Torres-Ruiz, R, Suela, J, Acquadro, F, Martin, M C, Yebra, E, Ramirez, J C, Alvarez, S, Cigudosa, J C
• Format: Article
• Language: English
• Subjects: 38; 38/32; 38/44; 38/77; 631/67/1990; Aged; Apoptosis; Cell Biology; Cell Differentiation - genetics; Cell Proliferation - genetics; Chromosomes; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Disease susceptibility; Gene mutations; Genes; Genetic aspects; Health aspects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Human Genetics; Humans; Identification and classification; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Medicine; Medicine & Public Health; Mutation; Oncology; original-article; Proteins; Risk factors; Translocation (Genetics); Translocation, Genetic
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.70

We have identified a new t(1;21)(p32;q22) chromosomal translocation in a MDS/AML patient that results in expression of an aberrant C-terminally truncated RUNX1 protein lacking several regulatory domains. As similar truncated RUNX1 proteins are generated by genetic aberrations including chromosomal translocations and point mutations, we used the t(1;21)(p32;q22) chromosomal translocation as a model to explore whether C-terminally truncated RUNX1 proteins trigger effects similar to those induced by well-characterized leukemogenic RUNX1 fusion genes. In vitro analysis of transduced human hematopoietic/progenitor stem cells showed that truncated RUNX1 proteins increase proliferation and self-renewal and disrupt the differentiation program by interfering with RUNX1b. These effects are similar to but milder than those induced by the RUNX1/ETO fusion protein. GSEA analysis confirmed similar altered gene expression patterns in the truncated RUNX1 and RUNX1/ETO models, with both models showing alterations in genes involved in self-renewal and leukemogenesis, including homeobox genes, primitive erythroid genes and leukemogenic transcription factors. We propose that C-terminally truncated RUNX1 proteins can contribute to leukemogenesis in a similar way to RUNX1 fusion genes but through a milder phenotype.