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, Samir Parekh

Research output: Contribution to journalArticle

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Abstract

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% to 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, because germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (Em-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B-cell–specific IgH-Em 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 (CD51CD191CD232) identical to human MCL. Furthermore, phosphocytometric time-of-flight analysis of the splenocytes from these mice shows hyperactivation 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.

Original languageEnglish (US)
Pages (from-to)2247-2255
Number of pages9
JournalBlood
Volume131
Issue number20
DOIs
StatePublished - May 17 2018

Fingerprint

Mantle-Cell Lymphoma
Tumors
B-Lymphocytes
Cells
Neoplasms
SOXC Transcription Factors
Bone
Transplants
Bone Marrow
Animals
Blood
Oncogenes
Molecules
Transgenic Mice
Hyperplasia
Lymphoma
Spleen
Animal Models
Tissue Donors
Phenotype

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kuo, P. Y., Jatiani, S. S., Rahman, A. H., Edwards, D., Jiang, Z., Ahr, K., ... Parekh, S. (2018). Sox11 augments bcr signaling to drive mcl-like tumor development. Blood, 131(20), 2247-2255. https://doi.org/10.1182/blood-2018-02-832535

Sox11 augments bcr signaling to drive mcl-like tumor development. / Kuo, Pei Yu; Jatiani, Shashidhar S.; Rahman, Adeeb H.; Edwards, Donna; Jiang, Zewei; Ahr, Katya; Perumal, Deepak; Leshchenko, Violetta V.; Brody, Joshua; Shaknovich, Rita; Ye, B. Hilda; Parekh, Samir.

In: Blood, Vol. 131, No. 20, 17.05.2018, p. 2247-2255.

Research output: Contribution to journalArticle

Kuo, PY, Jatiani, SS, Rahman, AH, Edwards, D, Jiang, Z, Ahr, K, Perumal, D, Leshchenko, VV, Brody, J, Shaknovich, R, Ye, BH & Parekh, S 2018, 'Sox11 augments bcr signaling to drive mcl-like tumor development', Blood, vol. 131, no. 20, pp. 2247-2255. https://doi.org/10.1182/blood-2018-02-832535
Kuo PY, Jatiani SS, Rahman AH, Edwards D, Jiang Z, Ahr K et al. Sox11 augments bcr signaling to drive mcl-like tumor development. Blood. 2018 May 17;131(20):2247-2255. https://doi.org/10.1182/blood-2018-02-832535
Kuo, Pei Yu ; Jatiani, Shashidhar S. ; Rahman, Adeeb H. ; Edwards, Donna ; Jiang, Zewei ; Ahr, Katya ; Perumal, Deepak ; Leshchenko, Violetta V. ; Brody, Joshua ; Shaknovich, Rita ; Ye, B. Hilda ; Parekh, Samir. / Sox11 augments bcr signaling to drive mcl-like tumor development. In: Blood. 2018 ; Vol. 131, No. 20. pp. 2247-2255.
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abstract = "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{\%} to 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, because germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (Em-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B-cell–specific IgH-Em 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 (CD51CD191CD232) identical to human MCL. Furthermore, phosphocytometric time-of-flight analysis of the splenocytes from these mice shows hyperactivation 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.",
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AU - Ahr, Katya

AU - Perumal, Deepak

AU - Leshchenko, Violetta V.

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