SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia
| Autor: | Alexander Richard, Jung-Hyun Kim, Nathan Ungerleider, Johnny Tran, Hannah K. Giannini, Hyun Kyung Kong, Eun Young Park, Erik K. Flemington, Ssang-Taek Lim, Melody Baddoo, Lana Vukadin, Eun-Young Erin Ahn, Joshua K. Stone |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research JUNB Gene Expression Biology Transfection Article Transcriptome Minor Histocompatibility Antigens 03 medical and health sciences Acute megakaryoblastic leukemia chemistry.chemical_compound 0302 clinical medicine Leukemia Megakaryoblastic Acute hemic and lymphatic diseases Gene expression medicine Humans Genetic Predisposition to Disease Enhancer Molecular Biology Gene knockdown Cell Differentiation medicine.disease Cell biology DNA-Binding Proteins 030104 developmental biology RUNX1 chemistry 030220 oncology & carcinogenesis Core Binding Factor Alpha 2 Subunit Molecular Medicine Down Syndrome Chromosome 21 Megakaryocytes |
| Zdroj: | Cancer gene therapy |
| ISSN: | 1476-5500 0929-1903 |
| Popis: | A high incidence of acute megakaryoblastic leukemia (AMKL) in Down syndrome patients implies that chromosome 21 genes have a pivotal role in AMKL development, but the functional contribution of individual genes remains elusive. Here, we report that SON, a chromosome 21-encoded DNA- and RNA-binding protein, inhibits megakaryocytic differentiation by suppressing RUNX1 and the megakaryocytic gene expression program. As megakaryocytic progenitors differentiate, SON expression is drastically reduced, with mature megakaryocytes having the lowest levels. In contrast, AMKL cells express an aberrantly high level of SON, and knockdown of SON induced the onset of megakaryocytic differentiation in AMKL cell lines. Genome-wide transcriptome analyses revealed that SON knockdown turns on the expression of pro-megakaryocytic genes while reducing erythroid gene expression. Mechanistically, SON represses RUNX1 expression by directly binding to the proximal promoter and two enhancer regions, the known +23 kb enhancer and the novel +139 kb enhancer, at the RUNX1 locus to suppress H3K4 methylation. In addition, SON represses the expression of the AP-1 complex subunits JUN, JUNB, and FOSB which are required for late megakaryocytic gene expression. Our findings define SON as a negative regulator of RUNX1 and megakaryocytic differentiation, implicating SON overexpression in impaired differentiation during AMKL development. |
| Databáze: | OpenAIRE |
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