Session: 621. Lymphoma—Genetic/Epigenetic Biology: Poster I
Hematology Disease Topics & Pathways:
Diseases, Lymphoma (any), Animal models, cell division, Mantle Cell Lymphoma, Non-Hodgkin Lymphoma, Biological Processes, Lymphoid Malignancies, Study Population, pathways
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.
Disclosures: Teruya-Feldstein: Edge Anthem: Consultancy. Parekh: Foundation Medicine: Consultancy; Celgene: Research Funding; Karyopharm: Research Funding.
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