Poster abstracts

Poster number 53 submitted by Anuvrat Sircar

Role of Fibroblast Growth Factor Receptor-1 in mediating growth and survival in Mantle Cell Lymphoma

Anuvrat Sircar (Molecular, Cellular and Developmental Biology Graduate program), Satishkumar Singh (Division of Hematology, Department of Internal Medicine, The Ohio State University), Evangelia Chavdoula (The Ohio State University Comprehensive Cancer Center), Philip N. Tsichlis (The Ohio State University Comprehensive Cancer Center), Lalit Sehgal (Division of Hematology, Department of Internal Medicine, The Ohio State University)

Abstract:
Mantle Cell Lymphoma (MCL) is an aggressive form of non-Hodgkin’s lymphoma, with late-onset, high progression rates, and extensive bone marrow (BM) involvement. Despite various treatment strategies, survival has not improved in MCL. Targeted therapy using ibrutinib improves overall survival; however, relapse occurs, with 30-50% of patients presenting with de-novo or acquired resistance (AIR), illustrating a desperate need for alternative druggable targets and therapy options. Our unbiased integrated whole transcriptome analyses identified Fibroblast Growth Factor Receptor-1 (FGFR1) as a novel mutually upregulated candidate gene in ibrutinib-resistant patient B-cells, patient-derived cells cultured under stromal support, and patient-derived cells compared to healthy B-cells. Consistent with our analysis, conditioned media from the BM stroma confers cellular proliferation and tumor survival via the FGFR1 signaling pathway. Using a wide array of techniques such as ChIP-enrichment analysis, RNA Sequencing, ChEA, ArCHS4, GO & KEGG pathway analysis, overexpression/knockdown, and rescue studies, along with in-vivo FGFR1 inhibition experiments utilizing MCL AIR and PDX models in both immunodeficient and immunocompetent mice backgrounds, we show that FGFR1 expression modulates decreased sensitivity to ibrutinib via regulation of the PRC2 complex, particularly EZH2, in conjunction with KDM2B, a histone demethylase. Furthermore, we show that the drug sensitivity and tumorigenicity are modulated downstream through EZH2 controlled effect on CDKN family members. Our data demonstrate that FGFR1 can be therapeutically targeted in MCL to attack ibrutinib resistant tumors and a better understanding of the molecular signaling involved in this process, a stepping-stone towards developing effective targeted therapies to cure patients with relapsed MCL.

Keywords: Mantle Cell Lymphoma, Bone-marrow microenvironment, Drug resistance