SOX11 augments BCR signaling to drive MCL-like tumor development

Pei-Yu Kuo, Shashidhar S. Jatiani, Adeeb H. Rahman, Donna Edwards, Zewei Jiang, Katya Ahr, Deepak Perumal, Violetta V. Leshchenko, Joshua Brody, Rita Shaknovich, B. Hilda Ye and Samir Parekh

Key points

  • B-cell specific overexpression of SOX11 promotes oncogenic proliferation of B1a B-cells and drives an MCL-like phenotype.

  • SOX11 overexpression is associated with increased signaling through the BCR pathway that can be reversed by pharmacological BTK inhibition.


Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78-93%) of MCL patients and is considered an MCL-specific oncogene. So far, attempts to understand SOX11 function in vivo have been hampered by the lack of appropriate animal models; since germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (Eμ-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B cell specific IgH-Eμ enhancer. The overexpression of SOX11 exclusively in B cells exhibits oligoclonal B cell hyperplasia in the spleen, bone marrow and peripheral blood, with an immunophenotype (CD5+CD19+CD23-) identical to human MCL. Further, phospho-CyTOF analysis of the splenocytes from these mice shows hyper-activation of pBTK and other molecules in the BCR signaling pathway and serial bone marrow transplant from transgenic donors produces lethality with decreasing latency. We report here that overexpression of SOX11 in B cells promotes BCR signaling and a disease phenotype that mimics human MCL.

  • Submitted February 9, 2018.
  • Accepted March 23, 2018.