Unraveling IKZF1 Deletion Therapeutic Vulnerabilities in Adult B-Cell Precursor Acute Lymphoblastic Leukemia

Context IKZF1 (Ikaros) deletion has been proposed as a poor prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP ALL) in children and adults. Objective To analyze the frequency and prognostic impact of IKZF1 deletions in adult BCP ALL patients. To identify the IKZF1 gene expression signature to find patients with different deletion isoforms and therapeutic opportunities. Patients and methods MLPA or SNP array samples of 151 (109 Ph-negative and 42 Ph+) adult BCP ALL patients treated with MRD-oriented protocols from the PETHEMA Group. RNAseq was performed in 48 of them (27 Ph-negative and 21 Ph+). Results Median age was 40 [15–72] years. Ph+ patients showed older age (52 [20;72] vs. 36 [15;68] years, p 1.5 in RNAseq data analysis, we identified a robust IKZF1 deletion gene expression profile. This resulted in 119 significantly upregulated genes after multi-comparison adjustment (i.e. CCND1, LAMA3, SLC2A9, SNAI1, LDHC, CD34, ID3, CDH2, MAF) and 39 downregulated genes (i.e. ROBO1, HES6, KREMEN1, DHCR24, ABHD15). Downregulated genes were involved in Slit/Robo/EMT, Notch, Wnt/beta-catenin, and glucose and fatty acid metabolism pathways, while upregulated genes were involved in focal adhesion, ROS homeostasis, histone modification, anaerobic metabolism, stem cell quiescence, and IL-6/STAT pathways. A significant number of dysregulated gene targets of chemotherapeutic agents (retinoic acid, doxorubicin, cisplatin, gemcitabine) and targeted therapies, such as FAKi, ERKi, BCL2i, mTORi, JAKi, BRKi, EGFRi and CDKi, were identified. Conclusions Adult BCP ALL patients with IKZF1 partial gene deletions showed poor prognosis. Gene expression analysis enables the identification of potentially targetable lesions. Funding Supported in part by a grant from the Instituto de Salud Carlos III, Ministerio de Economia y Competividad, Spain (PI14/01971); 2017 SGR288 (GRC) Generalitat de Catalunya; and support from CERCA Programme/Generalitat de Catalunya, Fundacio Internacional Josep Carreras. The research leading to this invention has received funding from “la Caixa” Foundation.