PT  - JOURNAL ARTICLE
AU  - Mei Wang
AU  - Qilong Chen
AU  - Hailing Liu
AU  - Hao Chen
AU  - Binbin Wang
AU  - Wubing Zhang
AU  - Ailu Mading
AU  - Wenjing Li
AU  - Shuangqi Li
AU  - Hang Liu
AU  - ZhongKai Gu
AU  - Shuxian Liu
AU  - Rui Guo
AU  - Wei Li
AU  - Tengfei Xiao
AU  - Feizhen Wu
TI  - CRISPR/Cas9 screens Reveal Dasatinib Targets of Inhibiting T cell Activation and Proliferation
AID  - 10.1101/448662
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 448662
4099  - http://biorxiv.org/content/early/2018/10/21/448662.short
4100  - http://biorxiv.org/content/early/2018/10/21/448662.full
AB  - Immune response by T cells is essential for a healthy body against cancer, infection, and pathophysiological alteration. The activation and expansion of T cells can be inhibited by dasatinib, a tyrosine inhibitor, thus improving the outcome of diseases, such as autoimmune disease, graft-versus-host disease, and transplant rejection. The underlying mechanism of inhibition by dasatinib is elusive. Here, we designed and synthesized a CRISPR/Cas9 screening library that includes 6,149 genes. Using the library, we performed dasatinib CRISPR/cas9 screening in Jurkat cell, a T lymphocyte cell. We firstly identified survival essential genes for Jurkat cells. Comparing with other CRISPR/Cas9 screenings, we obtained Jurkat cell specific essential genes. By comparing dasatinib treatment to control, we identified a set of dasatinib targets, which includes known targets: CSK, LCK, ZAP70, and previously unknown targets: ZFP36L2, LRPPRC, CFLAR, PD-1, CD45 et al. Visualizing these target genes on T cell receptor signaling pathway, we found several genes could be inhibited by dasatinib. Furthermore, we introduced a framework, 9-square, to classify genes and found a group of genes that are associated with dasatinib resistance, possibly linking the side effects of dasatinib. These data reveal a set of dasatinib targets and demonstrate the molecular potential functions of dasatinib. Identification of dasatinib targets will broaden our understanding to its molecular mechanism, and thus benefits to clinical outcome.