Abstract 2260: Evaluating a rare t(X;14)(q28;q32) translocation reveals MTCP1 as a driving factor in chronic lymphocytic leukemia

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western countries and is spelled by substantial genetic and clinical heterogeneity. During CLL transformation, loss or gain of genetic material appears to be a key determinant of disease phenotype and clinical outcome, with major chromosome aberrations observed in up to 80% of patients. Alternatively, balanced translocations, specifically those resulting in constitutive over-expression of various proto-oncogenes under the immunoglobulin heavy chain locus (IGH; 14q32), occur far less frequently. Despite their infrequence, molecular profiling of these rare rearrangements have revealed broad importance of un-recognized genes critical to the pathogenesis of CLL. Employing this strategy, we identified a young CLL patient with a previously undescribed t(X;14)(q28;q32) translocation, co-localization of the mature T cell proliferation 1 (MTCP1; Xq28) coding region with the IGH locus, triggering overexpression of MTCP1 in the CLL cells. Translocations involving MTCP1 are a driving factor in T-prolymphocytic leukemia; however, a role for MTCP1 in CLL has not been described. Inspired by this observation, we screened >1700 suspected CLL cases and evaluated gene expression data for further evidence of MCTP1 aberrations. This query identified seven additional Xq28 rearrangements, revealed MTCP1 mRNA was globally over-expressed in CLL cells compared to normal B-cells, and increased MTCP1 mRNA expression portends a poor response to chemoimmunotherapy. To establish a role for MTCP1 as an oncogene in B cell malignancies, we generated a mouse model with B cell-specific MTCP1 overexpression (Eµ-MTCP1). Longitudinal evaluation revealed a majority of Eµ-MTCP1 mice developed a lethal hematologic malignancy between 5-12 months of age, highlighted by the progressive emergence of clonally related CLL-like B lymphocytes (CD19+/CD5+ B cells) in the blood and accumulating in the spleen and lymph nodes. To support the use of the newly generated Eµ-MTCP1 mouse as a tool for pre-clinical evaluation of CLL therapeutics, we demonstrate that continuous ibrutinib administration in Eµ-MTCP1 mice was sufficient to delay the onset of the CLL-like disease and significantly prolonged survival. In summary, we report Xq28 translocations as rare genetic abnormalities in CLL, yet being one mechanism by which CLL cells amplify expression of MTCP1 compared to normal B cell subsets. Further, the Eµ-MTCP1 mouse model should be considered as an alternative tool for both biologic assessment of co-expressed genes and pre-clinical evaluation of novel CLL therapeutics. Lastly, relevant to all cancer types, successful application of a strategy pursuing the functional consequence of genes involved in rare translocations contributed to the understanding of this disease and identified a novel target for future therapeutic consideration. Citation Format: Janek S. Walker, Zachary A. Hing, Steven Sher, James Cronin, Katie Williams, Bonnie Harrington, Jordan N. Skinner, Casey B. Cempre, Charles T. Gregory, Max Yano, Larry P. Beaver, Brandi R. Walker, Jadwiga M. Labanowska, Nyla A. Heerema, Krzysztof Mrozek, Jennifer A. Woyach, Amy S. Ruppert, Amy Lehman, Hatice Gulcin Ozer, Vincenzo Coppola, John C. Byrd, James S. Blachly, Rosa Lapalombella. Evaluating a rare t(X;14)(q28;q32) translocation reveals MTCP1 as a driving factor in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2260.