Aberrant Cell Cycle Programming Confers Rapid Lethality in the EuSOX11+ CCND1 MCL Mouse Model

Mantle Cell Lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation. This hallmark oncogenic event transposes CCND1 (11q13) under the control of the immunoglobin heavy chain (IGH) locus (14q32) resulting in constitutive cyclin D1 expression. Although Cyclin D1 (CCND1) overexpression is a key hallmark of MCL, CCND1 overexpressing murine models do not effectively recapitulate the MCL phenotype. Our published data demonstrated that SOX11 binds and regulates components in multiple oncogenic pathways in MCL (Kuo et. al., Oncogene 2015). Furthermore, we recently demonstrated that SOX11 promotes BCR signaling to drive MCL-like pathogenesis utilizing a SOX11 overexpressing (Eu-SOX11) murine model (Kuo et. al., Blood 2018). Given that the majority of classic human MCL co-express CCND1 and SOX11, we hypothesize that these oncogenes may cooperate to drive the pathogenesis of classical MCL.

To study in vivo cooperation between CCND1 and SOX11, we crossed Eu-SOX11 mice with Eu-CCND1 mice to generate Eu-SOX11:CCND1 double transgenic (DT) mice. We have previously reported an significant increase in the fraction of CD5+CD19+CD23- MCL cells in the peripheral blood, spleens, lymph nodes and bone marrow of Eu-SOX11 mice and this fraction was further enhanced in DT mice (Fig.1A). We have now conducted a 2-year survival analysis on all 4 genotypes and found significantly reduced survival in DT as compared to Eu-SOX11 mice (Fig.1B). Median survival in DT mice is 16.5 months as compared to 19.7 months in Eu-SOX11 mice.

Taken together, our results demonstrate a B-cell specific in vivo cooperation between SOX11 and CCND1 towards promoting a lethal MCL phenotype. RNA sequencing of splenocytes from DT versus SOX11-Tg mice showed significant enrichment of E2F1 target genes (p<.02) as a top oncogenic pathway (Fig.1C). Our previous results with CDK4/6 inhibition demonstrate a profound reduction in S phase in MCL cells (Divakar et. al., Leukemia 2016).

We have developed small molecule SOX11 inhibitors using a SOX11-DNA homology model we built using the crystal structure of the SOX4-DNA binding domain as a template. SOX11 small molecular inhibitors in combination with CDK4 inhibitors will be used to further dissect the mechanism of cooperation between SOX11 and CCND1 and develop a therapeutic strategy for MCL that is mechanistically distinct from BTK or Bcl-2 inhibition.