Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor.
Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor.
复制标题
DOI：
10.1038/onc.2011.462
复制
发表时间：
2012-06-07
期刊：
影响因子：
8
通讯作者：
Saya, H.
中科院分区：
文献类型：
--
作者：
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.
肿瘤的起源细胞和决定起源细胞的因素仍不清楚。本研究通过逆转录病毒将Myc基因(N-Myc或c-Myc)导入小鼠骨髓细胞，建立了B前体急性淋巴细胞白血病/淋巴瘤(Pre-B ALL/LBL)小鼠模型。造血干细胞(HSCs)对N-Myc诱导的Pre-B-ALL/LBL的敏感性高于淋巴祖细胞、髓系祖细胞和承诺祖B细胞。在没有Ink4a和Arf的情况下，N-Myc可以直接从祖细胞B细胞中诱导出Pre-B-ALL/LBL。ARF在祖细胞B细胞中的表达高于Ink4a。此外，N-Myc还可从Arf−/−前体B细胞中诱导Pre-B ALL/LBL值，提示Arf在确定Pre-BALL/LBL值的细胞来源中起主导作用。Ink4a/Arf−/−前体B细胞来源的肿瘤细胞较野生型HSC来源的肿瘤细胞具有更高的增殖率和更强的化疗耐药性。此外，mdm2抑制剂Nutlin-3可使Ink4a/Arf−/−细胞来源的小鼠Pre-B-ALL/Lbl细胞和缺乏Ink4a/Arf基因表达的人B-ALL细胞系大量凋亡，提示抑制mdm2可能是治疗Ink4a/Arf−/−B-ALL/Lbl的一种新的治疗方法。总之，这些发现表明，Ink4a和Arf是Myc诱导的淋巴样肿瘤的起源细胞和治疗敏感性的关键决定因素。
The cell of origin of tumors and the 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 plays 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.
登录
查看更多内容
在儿童急性淋巴细胞白血病中，处于免疫表型成熟不同阶段的母细胞具有干细胞特性。
影响因子：
50.3
作者：
le Viseur C;Hotfilder M;Bomken S;Wilson K;Röttgers S;Schrauder A;Rosemann A;Irving J;Stam RW;Shultz LD;Harbott J;Jürgens H;Schrappe M;Pieters R;Vormoor J
通讯作者：
Vormoor J
影响因子：
82.9
作者：
Castor, A;Nilsson, L;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
20.3
作者：
Cox, CV;Evely, RS;Blair, A
通讯作者：
Blair, A
影响因子：
20.3
作者：
Morse, HC;Anver, MR;Ward, JM
通讯作者：
Ward, JM
影响因子：
20.3
作者：
Kojima, Kensuke;Konopleva, Marina;Andreeff, Michael
通讯作者：
Andreeff, Michael