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Understanding resistance mechanisms in cancer is of utmost importance for the discovery of novel “druggable” targets. Efficient genetic screening, now even more possible with CRISPR‐Cas9 gene‐editing technology, next‐generation sequencing and bioinformatics, is an important tool for deciphering novel cellular processes, such as resistance to treatment in cancer. Imatinib specifically eliminates chronic myeloid leukemia (CML) cells by targeting and blocking the kinase activity of BCR‐ABL1; however, resistance to treatment exists. In order to discover BCR‐ABL1 independent mechanisms of imatinib resistance, we utilized the genome‐scale CRISPR knock‐out library to screen for imatinib‐sensitizing genes in vitro on K562 cells. We revealed genes that seem essential for imatinib‐induced cell death, such as proapoptotic genes (BIM, BAX) or MAPK inhibitor SPRED2. Specifically, reestablishing apoptosis in BIM knock‐out (KO) cells with BH3 mimetics, or inhibiting MAPK signaling in SPRED2 KO cells with MEK inhibitors restores sensitivity to imatinib. In this work, we discovered previously identified pathways and novel pathways that modulate response to imatinib in CML cell lines, such as the implication of the Mediator complex, mRNA processing and protein ubiquitinylation. Targeting these specific genetic lesions with combinational therapy can overcome resistance phenotypes and paves the road for the use of precision oncology., We utilized a genome‐scale CRISPR library to discover genes and pathways that could potentially be the target of novel therapeutic strategies for overcoming resistance to imatinib in chronic myeloid leukemia in vitro.

International audience; Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin‐like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells. Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2. Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B‐positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32‐0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment‐free remission rates. Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte‐mediated control of leukemic residual disease control in patient with CML relapse.