| 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
|
| リソース情報 |
| ヒト・動物細胞 |
NALM-6(RCB1933)
HAL-01(RCB0540)
BALL-1(RCB0256)
Tanoue(RCB1180) |
