RRC ID 66864
Author Yokomizo-Nakano T, Kubota S, Bai J, Hamashima A, Morii M, Sun Y, Katagiri S, Iimori M, Kanai A, Tanaka D, Oshima M, Harada Y, Ohyashiki K, Iwama A, Harada H, Osato M, Sashida G.
Title Overexpression of RUNX3 Represses RUNX1 to Drive Transformation of Myelodysplastic Syndrome.
Journal Cancer Res
Abstract RUNX3, a RUNX family transcription factor, regulates normal hematopoiesis and functions as a tumor suppressor in various tumors in humans and mice. However, emerging studies have documented increased expression of RUNX3 in hematopoietic stem/progenitor cells (HSPC) of a subset of patients with myelodysplastic syndrome (MDS) showing a worse outcome, suggesting an oncogenic function for RUNX3 in the pathogenesis of hematologic malignancies. To elucidate the oncogenic function of RUNX3 in the pathogenesis of MDS in vivo, we generated a RUNX3-expressing, Tet2-deficient mouse model with the pancytopenia and dysplastic blood cells characteristic of MDS in patients. RUNX3-expressing cells markedly suppressed the expression levels of Runx1, a critical regulator of hemaotpoiesis in normal and malignant cells, as well as its target genes, which included crucial tumor suppressors such as Cebpa and Csf1r. RUNX3 bound these genes and remodeled their Runx1-binding regions in Tet2-deficient cells. Overexpression of RUNX3 inhibited the transcriptional function of Runx1 and compromised hematopoiesis to facilitate the development of MDS in the absence of Tet2, indicating that RUNX3 is an oncogene. Furthermore, overexpression of RUNX3 activated the transcription of Myc target genes and rendered cells sensitive to inhibition of Myc-Max heterodimerization. Collectively, these results reveal the mechanism by which RUNX3 overexpression exerts oncogenic effects on the cellular function of and transcriptional program in Tet2-deficient stem cells to drive the transformation of MDS. SIGNIFICANCE: This study defines the oncogenic effects of transcription factor RUNX3 in driving the transformation of myelodysplastic syndrome, highlighting RUNX3 as a potential target for therapeutic intervention.
Volume 80(12)
Pages 2523-2536
Published 2020-6-15
DOI 10.1158/0008-5472.CAN-19-3167
PII 0008-5472.CAN-19-3167
PMID 32341038
MeSH Animals Bone Marrow / pathology Cell Transformation, Neoplastic / genetics* Core Binding Factor Alpha 2 Subunit / metabolism* Core Binding Factor Alpha 3 Subunit / metabolism* DNA-Binding Proteins / genetics Dioxygenases Disease Models, Animal Hematopoietic Stem Cells / pathology* Humans Jurkat Cells Mice Mice, Knockout Myelodysplastic Syndromes / genetics Myelodysplastic Syndromes / pathology* Primary Cell Culture Proto-Oncogene Proteins / genetics Transcription, Genetic
IF 9.727
Human and Animal Cells 293T(RCB2202) Jurkat