A genome-wide CRISPR screen identifies genes critical for resistance to FLT3 inhibitor AC220

ABSTRACT: 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. In our screen, we identified SPRY3, an intracellular inhibitor of FGF signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated that re-activation of downstream FGF/Ras/ERK and Wnt signaling as major mechanisms of resistance to the FLT3 inhibitor. We also confirmed our findings in primary AML patient samples. We demonstrated that the expression level of SPRY3 and GSK3A is dramatically reduced in AC220 resistant AML samples and SPRY3 deleted primary AML cells are resistant to AC220. Intriguingly, we found that expression of SPRY3 is 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 confers resistance to a selective FLT3 inhibitor and revealed the underlying mechanism, thereby providing new insight into signaling pathways that contribute to the acquired resistance in AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98612 | GEO | 2017/05/06

SECONDARY ACCESSION(S): PRJNA385668

REPOSITORIES: GEO