Development of a Blastoid Variant, Mantle Cell Lymphoma Model in Transgenic Mice.

Mantle Cell Lymphoma (MCL) is a poorly understood, aggressive histotype of B-cell non-Hodgkin’s Lymphomas (NHL-B) that remains the most therapeutically resistant of the NHL-B. Little is known regarding why MCL is so clinically aggressive and therapeutically refractory. Blastoid variant MCL (MCL-BV) is an even more aggressive form of MCL that appears to be increasing in incidence in the US. It may represent progression from classic MCL, often with leukemic involvement and complex lymphoma karyotypes. Interleukin 14 (IL-14) is cytokine that was identified and cloned from a Burkitt lymphoma (BL) cell line that acts as a growth factor for normal B-lymphocytes. The expression of IL-14a protein and mRNA levels are elevated at lease fifty-fold in B-cell non-Hodgkin’s Lymphomas (NHL-B), including mantle cell lymphoma (MCL), in contrast to very low levels of IL-14a in quiescent (G_o) B cells by both western and northern blot analysis. To evaluate the role of IL-14 in vivo, we have generated transgenic mice expressing IL-14 with pEuSR. The IL-14 TG mice generally live a normal life span, however when autopsies are performed at 18 months of age, splenomegaly is noted, and 50% have evidence of B cell lymphoma. This lymphoma is CD5+, CD19+, sIgM+, CD21− and contains a monoclonal population of B-lymphocytes with rearranged immunoglobulin genes. Morphologically the lymphoma arising in IL-14 transgenic mice resembles the centroblastic/Immunoblastic histotype of DLBCL. Because of the frequent involvement of c-myc in various B cell malignancies, we crossed Eμ-myc (c-myc TG) mice with the IL-14 TG mice. By 3 months of age, 100% of the double transgenic (DTG) mice develop an aggressive B cell malignancy that is characterized by extensive lymphadenopathy and splenomegaly with intermediate to large atypical lymphoid cells, strongly resembling MCL-BV morphologically. This tumor, like that derived from the IL-14 TG mice, is CD5+, CD19+, sIgM+, CD21−. It is also CD23− and over-expresses Cyclin D1 in monoclonal B lymphoid cells with re-arranged IgH immunoglobulin genes, mimicking the MCL phenotype. At the time of autopsy, tumor infiltration of DTG mice is generally found in all organs evaluated, including peripheral blood, lymph nodes, spleen, liver, bone marrow, thymus and kidneys, consistent with the usual findings in MCL-BV. No tumors are observed in IL-14α TG or c-myc TG mice autopsied at this age. This MCL-BV model allows for the molecular and genotypic characterization of the murine B lymphoid cell compartment from birth to lymphoma development (3 mos.), including histogenesis and functional determination of the growth and survival characteristics of these tumors in DTG bone marrow and peripheral B cell populations. Preliminary comparative in vitro and in vivo (SCID Xeno-transplants) studies in DTG/MCL-BV lymphomas have shown additional molecular similarities to the pathophysiology (e.g constitutive NF-kB activation) of MCL-BV cell lines and patient samples, that should provide insights for future potential therapeutic approaches to MCL.