Targeting signaling pathways vulnerabilities for the treatment of IKZF1-deleted ph-negative B lymphoblastic leukemia.

• DOI: 10.1200/jco.2022.40.16_suppl.7033
• Publication Date: 2022-06-06T16:51:52Z
• Authors: Rohit Gupta; Jason H. Rogers; Xin Long; Rogelio Aguilar; Geraldo Medrano; Jaime Reyes; Michele Redell; Margaret A. Goodell; Rachel E. Rau
• Keywords: Ruxolitinib

7033 Background: Approximately 20% of children diagnosed with B lymphoblastic leukemia (B-ALL) will suffer a relapse, and most adults B-ALL have poor prognosis. Genome-wide association studies patients identified frequent deletions the gene IKZF1, encoding master regulator lymphoid development, IKAROS. These are associated therapy resistance, increased risk inferior survival. Currently, how loss IKAROS function contributes to resistance relapse is not fully understood. We used CRISPR-Cas9 genome editing develop human cell lines various IKZF1 that genetically phenotypically recapitulate those occurring in patients. Using these isogenic lines, we previously shown deletion results cell-intrinsic chemoresistance activation JAK/STAT signaling pathway (Rogers, Gupta et al. 2021). Methods: Given often dysregulated poor-prognosis leukemia, investigated potential mechanisms aberrant therapeutic targeting our engineered lines. treated cells SH-4-54 (STAT3/5 inhibitor) or tofacitinib (JAK1 alone combination dexamethasone. To elucidate mediates an increase JAK-STAT activity, also performed RNAseq known regulators, comparing wild-type knockout. Results: The negative Suppressor Cytokine Signaling 2 (SOCS2) was significantly downregulated deletion, validated by RTqPCR immunoblotting. further analyzed publicly-available data from > 650 pediatric samples, finding SOCS2 expression lower low IKZF1expression (likely corresponding deletion) compared high expression. When SH-4-54, were sensitive each compound, suggesting plays vital role In contrast, IKZF1-deleted relatively resistant inhibitors alone. However, dexamethasone, treatment sub-IC50 levels resulted re-sensitization glucocorticoid-induced apoptosis. Conclusions: Our findings support leads targetable upregulation that, when inhibited, relative deleted may be mediated decreased SOCS2. provide initial promise for vulnerabilities this disease.