Poster abstracts

Poster number 69 submitted by Anuvrat Sircar

Therapeutic targeting of de-novo and acquired drug resistance 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), Georgios Laliotis, Evangelia Chavdoula (Department of Cancer Biology and Genetics, The Ohio State University), Amber Hart (Division of Hematology, Department of Internal Medicine, The Ohio State University), Philip N. Tsichlis (Department of Cancer Biology and Genetics, The Ohio State University), Lalit Sehgal (Division of Hematology, Department of Internal Medicine, The Ohio State University)

Abstract:
Mantle Cell Lymphoma (MCL) is a rare but aggressive form of Non-Hodgkin’s lymphoma, with late-onset, high progression rates, & extensive bone marrow (BM) involvement. There is a high propensity towards development of drug resistance against treatment options presently available for MCL. One of these drugs is ibrutinib, a Bruton’s Tyrosine Kinase (BTK) inhibitor. Ibrutinib resistance is fairly common in MCL, with 30-50% of patients presenting with de-novo or acquired ibrutinib resistance (AIR). There is a dire need for alternative targets & therapy options. The BM provides a secure niche for MCL cells to thrive. Our data shows that BM microenvironment (BME) confers tumor survival & de-novo ibrutinib resistance in MCL. 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, & patient-derived cells compared to healthy B-cells. FGFR1 upregulation has been observed in both de-novo & AIR models, & correlates to a poorer prognosis. Our unbiased ChiP Enrichment Analysis (ChEA) identifies over-representation of histone demethylase KDM2B in MCL patient-derived cells compared to healthy B-cells, & further enhanced expression under stromal support promoting de-novo resistance. KDM2B expression is also elevated in AIR models. FGFR1 expression positively regulates KDM2B, & inhibition/loss of either FGFR1 or KDM2B re-sensitizes resistant cells to ibrutinib. FGFR1 inhibition in an ibrutinib resistant MCL xenograft murine model showed reduced tumor burden & prolonged survival time. Cytokine array performed to identify specific cytokine upregulation in stromal milieu, identified IL-6 as a major upregulated cytokine in BM stroma-conditioned media, with IL-6 seen to enhance FGFR1 expression. Stromal IL-6 knockdown or FGFR1 inhibition in BM stroma reversed the tumor-imparted MCL tumor growth advantage. MCL culture in IL-6 knockout mouse stroma reversed the stroma imparted ibrutinib resistance. These results indicate the vitality of IL6-FGFR1-KDM2B axis in tumor progression & drug resistance, shedding light on mechanisms for BME mediated tumor survival, paving way for identification of new druggable targets.

References:
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Keywords: Mantle Cell Lymphoma, Bone-marrow microenvironment, drug resistance