Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia

达沙替尼 威尼斯人 癌症研究 白血病 T细胞 离体 淋巴细胞白血病 医学 生物 Jurkat细胞 髓系白血病 免疫学 体内 慢性淋巴细胞白血病 伊马替尼 遗传学 免疫系统
作者
Yoshihiro Gocho,Jingjing Liu,Jianzhong Hu,Wentao Yang,Neekesh V. Dharia,Jingliao Zhang,Hao Shi,Guoqing Du,August John,Ting-Nien Lin,Jeremy P. Hunt,Xin Huang,Bensheng Ju,Lauren Rowland,Lei Shi,Dylan Maxwell,Brandon Smart,Kristine R. Crews,Wenjian Yang,Kohei Hagiwara
出处
期刊:Nature cancer [Nature Portfolio]
卷期号:2 (3): 284-299 被引量:99
标识
DOI:10.1038/s43018-020-00167-4
摘要

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy and new therapeutics are much needed. Profiling patient leukemia drug sensitivities ex vivo, we discovered that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR–LCK activation as the driver of dasatinib sensitivity and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALL exhibited high BCL-XL activity, low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK versus BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR–LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy. Yang and colleagues perform a network system–pharmacology approach and clinical data integration, and identify LCK and BCL2 signaling as the molecular determinants of dasatinib response in pediatric and adult patients with T-ALL.
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