Mantle Cell Lymphoma (MCL) is an aggressive, typically fatal subtype of B-cell Non-Hodgkin's Lymphoma (NHL) characterized by t(11;14) leading to Cyclin D1 (CCND1) overexpression, a key diagnostic feature of this disease. However, murine models over-expressing CCND1 do not develop B-cell lymphoproliferation characteristically seen in human MCL. The SOX11 transcription factor is overexpressed in >90% of MCL tumor samples and associated with poor prognosis, however understanding of SOX11 function in vivo has been limited by a lack of animal models. We have therefore developed, extensively characterized and published our E?-SOX11-EGFP mouse model in Blood 2018 May 17;131(20):2247-2255. E?-SOX11-EGFP mice develop an increase in clonal B cells in the spleen, bone marrow and peripheral blood, with an aberrant immunophenotype (CD5+CD19+CD23-) and increased BCR signaling identical to human MCL. To accurately model human MCL, where both CCND1 and SOX11 are overexpressed, we have now developed an additional MCL mouse model by crossing E?-CCND1 mice with E?-SOX11-EGFP. The SOX11-induced phenotype we observe in E?-SOX11-EGFP mice is dramatically enhanced in the double transgenic mice, leading to a lethal phenotype with significantly reduced survival as compared to Eu-SOX11 mice. Our overall hypothesis is that the overexpression of SOX11 increases BCR signaling and cooperates with CCND1 through its transcriptional targets in MCL pathogenesis. To test our hypothesis, in Aim 1, we define the mechanism by which SOX11 increases BCR signaling in MCL.
In Aim 2, we will determine efficacy of molecular probes inhibiting SOX11-DNA binding in vitro and in vivo models of BTKi or BCL2i resistant MCL.
In Aim 3, we determine the mechanism by which SOX11 cooperates with CCND1 in vitro and in vivo to drive MCL. The therapeutic advantages of inhibiting SOX11 may be substantial, as the majority of MCL patients still relapse after immune-chemotherapy and die despite the advent of novel targeted therapeutics such as BTKi or BCL2i. We have recently identified through structural modeling of SOX11, a family of novel small molecule probes that inhibit the SOX11-DNA interaction with potent anti-MCL cytotoxicity in vitro. We have exciting preliminary data consistent with our hypothesis to demonstrate that SOX11i can overcome BTKi and BCL2i resistance in vitro. Prof. Michael Wang, a leading MCL researcher and a co-investigator in this proposal, has developed patient- derived BTKi-resistant and BCL2i-resistant primary MCL cells and corresponding PDX murine models. Our proposal brings together complementary elements including unique transgenic animal models, unique molecular probes inhibiting SOX11, patient-derived primary MCL models resistant to current standard of care, and functional studies for expanding our understanding of MCL pathogenesis to identify new targets and therapeutic options for patients with this challenging disease.
Mantle Cell Lymphoma is an aggressive and usually fatal subtype of Non-Hodgkin's Lymphoma whose pathogenesis is poorly understood, and new therapeutic options are urgently needed to improve the care of MCL patients. The transcription factor SOX11 is over-expressed in over 90% of MCL tumors and is associated with poor prognosis. Using a combinatorial approach that incorporates novel mouse models of MCL, small molecule SOX11 inhibitors, Ibrutinib(BTKi) and/or Venetoclax(BCL2i) resistant primary samples and PDX models, this application will define the role of SOX11 overexpression in MCL and explore the utility of inhibiting SOX11 directly as a novel therapeutic avenue for this incurable disease.
