Abstract 4955: Heterogeneous nuclear ribonucleoprotein C as a novel therapeutic target for acute myeloid leukemia

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Abstract Acute myeloid leukemia (AML) is a highly refractory cancer despite conventional treatment. Previously, we found that blood vessels are sanctuary sites for chemo-refractory AML cells. To target AML cells sequestered in the vascular niche, we developed an in vitro co-culture assay consisting of AML cells on bone marrow- derived endothelial cells (BMECs), mimicking the chemo-protective effect of the vascular niche in the bone marrow microenvironment. Using this assay, we performed high-throughput chemical-phenotypic screening of 31 million compounds and identified a novel polyamine sulfonamide (2470-51) that selectively killed AML cells, while sparing the underlying BMECs. 2470-51 was also cytotoxic to CD34+CD38-CD123+ AML stem cells; however, the compound was non-toxic to hematopoietic stem/progenitor cells and T lymphocytes from healthy volunteers. In vivo AML patient-derived xenograft modeling further validated the efficacy of 2470-51 as a selective anti-leukemic agent compared to cytarabine (conventional control) and vehicle control. Protein target identification experiments using unbiased label-free shotgun proteomic analysis in combination with targeted selected ion monitoring revealed heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) as the covalent target of 2470-51. These findings were further validated by shRNA mediated knock-down of HNRNPC (HNRNPC-kd) in AML cell lines THP-1 and K562. HNRNPC-kd significantly reduced AML cell proliferation as well as AML cell viability by inducing apoptosis, compared to scramble controls. HNRNPC-kd also significantly reduced the clonogenic potential of both AML cell lines. In contrast, normal mesenchymal/fibroblastic (HS5) and endothelial cells (BMECs) were unaffected by HNRNPC-kd, indicating the selective dependence of AML cells on hnRNPC. RNA-Seq analyses revealed alternative splice events associated with HNRNPC-kd. Functional enrichment analyses followed by pathway analyses indicated the involvement of hnRNPC in key oncogenic and cell survival pathways. Depleting hnRNPC significantly altered the post-transcriptional landscape, leading to induction of apoptosis. Clinical studies using TCGA AML datasets showed significant survival advantage associated with lower HNRNPC expression. Collectively, our data indicate that hnRNPC is a critical factor in AML and that inhibiting this splicing repressor may be a new therapeutic strategy. Citation Format: Vindhya Vijay, Amy Meacham, Jesse Terrell, Lauren Katzell, Leylah Drusbosky, Christopher Cogle. Heterogeneous nuclear ribonucleoprotein C as a novel therapeutic target for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4955.