Clonal Evolution Enhances Leukemia-Propagating Cell Frequency in T Cell Acute Lymphoblastic Leukemia through Akt/mTORC1 Pathway Activation

被引：101

作者：

Blackburn, Jessica S. ^{[1
,2
,3
]}

Liu, Sali ^{[4
]}

Wilder, Jayme L. ^{[3
]}

Dobrinski, Kimberly P. ^{[5
]}

Lobbardi, Riadh ^{[1
,2
,3
]}

Moore, Finola E. ^{[1
,2
,3
]}

Martinez, Sarah A. ^{[1
,2
]}

Chen, Eleanor Y. ^{[1
,2
,3
,6
]}

Lee, Charles ^{[7
,8
]}

Langenau, David M. ^{[1
,2
,3
]}

机构：

[1] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[3] Harvard Stem Cell Inst, Boston, MA 02138 USA

[4] Northwestern Univ, Chicago, IL 60208 USA

[5] Univ S Florida, Ctr Integrat Med, Tampa, FL 33620 USA

[6] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA

[7] Jackson Lab Genom Med, Farmington, CT 06030 USA

[8] Seoul Natl Univ, Sch Med, Dept Grad Studies, Seoul 110744, South Korea

来源：

CANCER CELL | 2014年 / 25卷 / 03期

基金：

美国国家卫生研究院;

关键词：

GLUCOCORTICOID RESISTANCE; INHIBITOR NVP-BEZ235; PTEN; MYC; HETEROGENEITY; TRANSPLANTATION; TRIAL;

D O I：

10.1016/j.ccr.2014.01.032

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia-propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, which increased the number of leukemia-propagating cells through activating mTORC1, elevated growth rate likely by stabilizing the Myc protein, and rendered cells resistant to dexamethasone, which was reversed by combined treatment with an Akt inhibitor. Thus, T-ALL clones spontaneously and continuously evolve to drive leukemia progression even in the absence of therapy-induced selection.

引用

页码：366 / 378

页数：13

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