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Gene expression signatures of C-terminal shorter RUNX1 protein hematopoietic models

ABSTRACT: RUNX1 gene chromosomal translocations and mutations are frequent in acute myeloid leukaemia, sometimes resulting in the aberrant expression of C-terminal-truncated RUNX1 proteins lacking the transactivation domain (TAD). Some AML patients anomalously over-express a RUNX1a splice variant with the same TAD deficit. We performed an in-depth in vitro study of the role of TAD-defective RUNX1 proteins in AML development in human hematopoietic/progenitor stem cells. Transformation ability, maturation phenotype and differentiation/proliferation effects were assessed. Short RUNX1 protein expression seemed to increase both proliferation and self-renewal capacity, disrupting the differentiation program and interfering with wild-type RUNX1b protein, in a dominant-negative, dose-dependent manner. Expression microarray analysis showed short RUNX1 and RUNX1/ETO models had similar aberrant expression patterns. Genes known to be broadly involved in self-renewal and leukemogenesis were found to be altered; specifically observed were overexpression of homeobox genes, downregulation of primitive erythroid genes and alterations in leukemogenic transcription factors. The Wnt/b-catenin and RhoA pathways were also observed to be altered, whereas short RUNX1 proteins appeared not to affect the Notch1 pathway, which is altered in the RUNX1/ETO model. Therefore, we propose that TAD-defective RUNX1 proteins may contribute to leukemogenesis and could form the basis of a new genetic category of AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48523 | GEO | 2014/01/01

SECONDARY ACCESSION(S): PRJNA210429

REPOSITORIES: GEO

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Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. This SuperSeries is composed of the following subset Series: GSE29222: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [ChIP-Seq and DNAse-Hypersensitivity data] GSE29223: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [expression array data] GSE34540: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (ChIP-seq) GSE34594: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (Illumina expression) Refer to individual Series

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Gene expression signatures of C-terminal shorter RUNX1 protein hematopoietic models

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