title: Truncated RUNX1 protein generated by a novel t(1;21)(p32;q22) chromosomal translocation impairs the proliferation and differentiation of human hematopoietic progenitors.
abstract: 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.
authors: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
authors: S
authors: S
authors: Rodriguez-Perales
authors: Viral Vector Technical Unit, Fundación Centro Nacional de Investigaciones Cardiovascular (CNIC), Madrid, Spain.
authors: R
authors: R
authors: Torres-Ruiz
authors: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
authors: J
authors: J
authors: Suela
authors: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
authors: F
authors: F
authors: Acquadro
authors: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
authors: M C
authors: MC
authors: Martin
authors: Hematology Service, Hospital Severo Ochoa, Madrid, Spain.
authors: E
authors: E
authors: Yebra
authors: Viral Vector Technical Unit, Fundación Centro Nacional de Investigaciones Cardiovascular (CNIC), Madrid, Spain.
authors: J C
authors: JC
authors: Ramirez
authors: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
authors: S
authors: S
authors: Alvarez
authors: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
authors: J C
authors: JC
authors: Cigudosa
mesh_terms: D000368:Aged; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D014178:Translocation, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human