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Hou P , Wu C , Wang Y , Qi R , Bhavanasi D , Zuo Z , Dos Santos C , Chen S , Chen Y , Zheng H , Wang H , Perl A , Guo D , Huang J
A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220
Cancer Res. 2017 Aug 15;77(16) :4402-4413
PMID: 28625976    PMCID: PMC5559306   
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Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. The mechanisms underlying drug resistance in AML are poorly understood. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most common molecular abnormality in AML. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3-ITD-positive and -negative AML patients and as maintenance therapy. To understand the mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR-pooled library to screen new genes whose loss of function confers resistance to AC220. We identified SPRY3, an intracellular inhibitor of FGF signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated reactivation of downstream FGF/Ras/ERK and Wnt signaling as major mechanisms of resistance to AC220. We confirmed these findings in primary AML patient samples. Expression of SPRY3 and GSK3A was dramatically reduced in AC220-resistant AML samples, and SPRY3-deleted primary AML cells were resistant to AC220. Intriguingly, expression of SPRY3 was greatly reduced in GSK3 knockout AML cells, which positioned SPRY3 downstream of GSK3 in the resistance pathway. Taken together, our study identified novel genes whose loss of function conferred resistance to a selective FLT3 inhibitor, providing new insight into signaling pathways that contribute to acquired resistance in AML. Cancer Res; 77(16); 4402-13. (c)2017 AACR.
1538-7445 Hou, Panpan Wu, Chao Wang, Yuchen Qi, Rui Bhavanasi, Dheeraj Zuo, Zhixiang Dos Santos, Cedric Chen, Shuliang Chen, Yu Zheng, Hong Wang, Hong Perl, Alexander Guo, Deyin Huang, Jian K99 HL107747/HL/NHLBI NIH HHS/United States R00 HL107747/HL/NHLBI NIH HHS/United States Journal Article United States Cancer Res. 2017 Aug 15;77(16):4402-4413. doi: 10.1158/0008-5472.CAN-16-1627. Epub 2017 Jun 16.