Abstract 1145: Zhx2 promotes survival of B-cell acute lymphoblastic leukemia cell lines

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Abstract Zhx2, a zinc finger containing transcription factor is frequently overexpressed in B cell malignancies including B cell acute lymphoblastic leukemia (B-ALL), however its role in development of B cell malignancies remains unknown. Previously, dysregulated activity of transcription factors due to mutation e.g. Myc or overexpression e.g. Sox11 has been shown to perturb B cell differentiation leading to malignant phenotypes, resistance to chemotherapeutics and genetic heterogeneity. Zhx2 is required for normal neuronal and erythropoietic differentiation and has been identified as a tumor suppressor in hepatocellular carcinoma. Furthermore, analysis of public databases shows that Zhx2 is highly overexpressed in several cell lines representing B cell malignancies including B cell acute lymphoblastic leukemia (B-ALL) and B cell lymphoma. Consistently, Zhx2 is also overexpressed in patient samples derived from different subtypes of B cell malignancies. Quantification of Zhx2 mRNA expression obtained from human donors showed a marked upregulation during transition from common lymphoid progenitor to Pro B-cell stage suggesting potential role in B cell differentiation. Here we report that Zhx2 is overexpressed in Philadelphia chromosome positive (Ph+) B-ALL and T-ALL cell lines as well as Ph- B-ALL cell line. Zhx2 silencing in BV-173 (Ph+ B-ALL) and CMLT1 (Ph+ T-ALL) showed enhanced apoptosis with low doses of Dasatinib, a dual Src/Abl kinase inhibitor. Furthermore, global gene promoter and gene expression analysis on Zhx2 silenced cells identified putative Zhx2 regulated genes including CREB and YY1. Both of these transcription factors have roles in B cell differentiation, survival, proliferation and are commonly deregulated in B cell malignancies. We propose that Zhx2 regulates a B cell differentiation program and that overexpression of Zhx2 could lead to blocked differentiation of B cell progenitors promoting the malignant phenotype. Therefore, Zhx2 could be exploited as a chemo-therapeutic target in B cell malignancies. Citation Format: Namit Sharma, Huayun Hou, Michael D. Wilson, Catherine Jane McGlade. Zhx2 promotes survival of B-cell acute lymphoblastic leukemia cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1145.