# Targeting SOX11 in Mantle Cell Lymphoma

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $550,887

## Abstract

Project Summary
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
Eμ-SOX11-EGFP mouse model in Blood 2018 May 17;131(20):2247-2255. Eμ-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 Eμ-CCND1 mice with Eμ-SOX11-EGFP. The SOX11-induced
phenotype we observe in Eμ-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.

## Key facts

- **NIH application ID:** 10410568
- **Project number:** 5R01CA252222-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Samir Parekh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $550,887
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410568

## Citation

> US National Institutes of Health, RePORTER application 10410568, Targeting SOX11 in Mantle Cell Lymphoma (5R01CA252222-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10410568. Licensed CC0.

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