論文 - 詳細
| RRC ID | 58052 |
|---|---|
| 著者 | Bai J, Yokomizo-Nakano T, Kubota S, Sun Y, Kanai A, Iimori M, Harada H, Iwama A, Sashida G. |
| タイトル | Overexpression of Hmga2 activates Igf2bp2 and remodels transcriptional program of Tet2-deficient stem cells in myeloid transformation. |
| ジャーナル | Oncogene |
| Abstract |
High Mobility Group AT-hook 2 (HMGA2) is a chromatin modifier and its overexpression has been found in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Level of Hmga2 expression is fine-tuned by Lin28b-Let-7 axis and Polycomb Repressive Complex 2, in which deletion of Ezh2 leads to activation of Hmga2 expression in hematopoietic stem cells. To elucidate the mechanisms by which the overexpression of HMGA2 helps transformation of stem cells harboring a driver mutation of TET2, we generated an Hmga2-expressing Tet2-deficient mouse model showing the progressive phenotypes of MDS and AML. The overexpression of Hmga2 remodeled the transcriptional program of Tet2-deficient stem and progenitor cells, leading to the impaired differentiation of myeloid cells. Furthermore, Hmga2 was bound to a proximal region of Igf2bp2 oncogene, and activated its transcription, leading to enhancing self-renewal of Tet2-deficient stem cells that was suppressed by inhibition of the DNA binding of Hmga2. These combinatory effects on the transcriptional program and cellular function were not redundant to those in Tet2-deficient cells. The present results elucidate that Hmga2 targets key oncogenic pathways during the transformation and highlight the Hmga2-Igf2bp2 axis as a potential target for therapeutic intervention. |
| 巻・号 | 40(8) |
| ページ | 1531-1541 |
| 公開日 | 2021-2-1 |
| DOI | 10.1038/s41388-020-01629-w |
| PII | 10.1038/s41388-020-01629-w |
| PMID | 33452460 |
| MeSH | Animals Cell Differentiation / genetics DNA-Binding Proteins / genetics* Dioxygenases Enhancer of Zeste Homolog 2 Protein / genetics Gene Expression Regulation, Neoplastic HMGA2 Protein / genetics* Humans Leukemia, Myeloid, Acute / genetics* Leukemia, Myeloid, Acute / pathology Mice MicroRNAs / genetics Myelodysplastic Syndromes / genetics* Myelodysplastic Syndromes / pathology Myeloid Cells / metabolism Myeloid Cells / pathology Polycomb Repressive Complex 2 / genetics Proto-Oncogene Proteins / genetics* RNA-Binding Proteins / genetics* |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Jurkat |