Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

被引:49
作者
Dail, Monique [1 ]
Li, Qing [2 ]
McDaniel, Andrew [1 ]
Wong, Jason [1 ]
Akagi, Keiko [5 ]
Huang, Ben [1 ]
Kang, Hio Chung [1 ]
Kogan, Scott C. [3 ]
Shokat, Kevan [4 ]
Wolff, Linda [6 ]
Braun, Benjamin S. [1 ]
Shannon, Kevin [1 ]
机构
[1] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
[5] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[6] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
K-ras; retroviral insertional mutagenesis; T cell leukemia; targeted therapeutics; Ikaros; ACUTE LYMPHOBLASTIC-LEUKEMIA; PROVIRUS INSERTIONAL MUTAGENESIS; K-RAS; CELL LEUKEMOGENESIS; MOLECULAR-GENETICS; SOMATIC ACTIVATION; TRANSGENIC MICE; ONCOGENIC KRAS; C-MYC; MUTATIONS;
D O I
10.1073/pnas.1001064107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras(G12D) mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes KrasG12D expression and later acquisition of somatic Notch1 mutations. Importantly, biochemical analysis uncovered unexpected heterogeneity, which suggests that Ras signaling networks are remodeled during multistep tumorigenesis. We tested tumor-derived cell lines to identify biomarkers of therapeutic response to targeted inhibitors. Whereas all T-ALLs tested were sensitive to a dual-specificity phosphoinosityl 3-kinase/mammalian target of rapamycin inhibitor, biochemical evidence of Notch1 activation correlated with sensitivity to gamma-secretase inhibition. In addition, Kras(G12D) T-ALLs were more responsive to a MAP/ERK kinase inhibitor in vitro and in vivo. Together, these studies identify a genetic pathway involving Ikzf1, Kras(G12D), and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies.
引用
收藏
页码:5106 / 5111
页数:6
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