論文 - 詳細
| RRC ID | 38427 |
|---|---|
| 著者 | Sugihara E, Shimizu T, Kojima K, Onishi N, Kai K, Ishizawa J, Nagata K, Hashimoto N, Honda H, Kanno M, Miwa M, Okada S, Andreeff M, Saya H. |
| タイトル | Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor. |
| ジャーナル | Oncogene |
| Abstract |
The cell of origin of tumors and the factors determining the cell of origin remain unclear. In this study, a mouse model of precursor B acute lymphoblastic leukemia/lymphoma (pre-B ALL/LBL) was established by retroviral transduction of Myc genes (N-Myc or c-Myc) into mouse bone marrow cells. Hematopoietic stem cells (HSCs) exhibited the highest susceptibility to N-Myc-induced pre-B ALL/LBL versus lymphoid progenitors, myeloid progenitors and committed progenitor B cells. N-Myc was able to induce pre-B ALL/LBL directly from progenitor B cells in the absence of Ink4a and Arf. Arf was expressed higher in progenitor B cells than Ink4a. In addition, N-Myc induced pre-B ALL/LBL from Arf(-/-) progenitor B cells suggesting that Arf has a predominant role in determining the cell of origin of pre-B ALL/LBL. Tumor cells derived from Ink4a/Arf(-/-) progenitor B cells exhibited a higher rate of proliferation and were more chemoresistant than those derived from wild-type HSCs. Furthermore, the Mdm2 inhibitor Nutlin-3 restored p53 and induced massive apoptosis in mouse pre-B ALL/LBL cells derived from Ink4a/Arf(-/-) cells and human B-ALL cell lines lacking Ink4a and Arf expression, suggesting that Mdm2 inhibition may be a novel therapeutic approach to the treatment of Ink4a/Arf(-/-) B-ALL/LBL, such as is frequently found in Ph(+) ALL and relapsed ALL. Collectively, these findings indicate that Ink4a and Arf are critical determining factors of the cell of origin and the therapeutic sensitivity of Myc-induced lymphoid tumors. |
| 巻・号 | 31(23) |
| ページ | 2849-61 |
| 公開日 | 2012-6-7 |
| DOI | 10.1038/onc.2011.462 |
| PII | onc2011462 |
| PMID | 21986948 |
| PMC | PMC3271180 |
| MeSH | Animals Antimetabolites, Antineoplastic / pharmacology Apoptosis / drug effects Blotting, Western Bone Marrow Cells / cytology Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism Bone Marrow Transplantation Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16 / physiology* Cytarabine / pharmacology* Disease Models, Animal Flow Cytometry Genes, myc* Hematopoietic Stem Cells / cytology Hematopoietic Stem Cells / drug effects Hematopoietic Stem Cells / metabolism Humans Imidazoles / pharmacology* Mice Mice, Knockout Piperazines / pharmacology* Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy* Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / etiology Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology* Precursor Cells, B-Lymphoid / cytology Precursor Cells, B-Lymphoid / drug effects Precursor Cells, B-Lymphoid / metabolism Tumor Suppressor Protein p14ARF / physiology* |
| IF | 7.971 |
| 引用数 | 16 |
| WOS 分野 | GENETICS & HEREDITY ONCOLOGY BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| 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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| 各媒体での言及数の合計 | 0 |
| 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 | NALM-6(RCB1933) HAL-01(RCB0540) BALL-1(RCB0256) Tanoue(RCB1180) |