SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia

Parham Ramezani-Rad, Huimin Geng, Christian Hurtz, Lai N. Chan, Zhengshan Chen, Hassan Jumaa, Ari Melnick, Elisabeth M. Paietta, William L. Carroll, Cheryl L. Willman, Véronique Lefebvre, Markus Mus̈chen

Research output: Contribution to journalArticle

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Abstract

The Sox4 transcription factor mediates early B-cell differentiation. Compared with normal pre-B cells, SOX4 promoter regions in Ph+ ALL cells are significantly hypomethylated. Loss and gain-of-function experiments identified Sox4 as a critical activator of PI3K/AKT and MAPK signaling in ALL cells. ChIP experiments confirmed that SOX4 binds to and transcriptionally activates promoters of multiple components within the PI3K/AKT and MAPK signaling pathways. Cre-mediated deletion of Sox4 had little effect on normal pre-B cells but compromised proliferation and viability of leukemia cells, which was rescued by BCL2L1 and constitutively active AKT and p110 PI3K. Consistent with these findings, high levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). Collectively, these studies identify SOX4 as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL.

Original languageEnglish (US)
Pages (from-to)148-155
Number of pages8
JournalBlood
Volume121
Issue number1
DOIs
StatePublished - Jan 3 2013

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Phosphatidylinositol 3-Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphoid Precursor Cells
Cells
Pediatrics
Genetic Promoter Regions
Cell Differentiation
Cell Survival
Leukemia
B-Lymphocytes
Transcription Factors
Experiments
Cell Proliferation
Clinical Trials

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Ramezani-Rad, P., Geng, H., Hurtz, C., Chan, L. N., Chen, Z., Jumaa, H., ... Mus̈chen, M. (2013). SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood, 121(1), 148-155. https://doi.org/10.1182/blood-2012-05-428938

SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. / Ramezani-Rad, Parham; Geng, Huimin; Hurtz, Christian; Chan, Lai N.; Chen, Zhengshan; Jumaa, Hassan; Melnick, Ari; Paietta, Elisabeth M.; Carroll, William L.; Willman, Cheryl L.; Lefebvre, Véronique; Mus̈chen, Markus.

In: Blood, Vol. 121, No. 1, 03.01.2013, p. 148-155.

Research output: Contribution to journalArticle

Ramezani-Rad, P, Geng, H, Hurtz, C, Chan, LN, Chen, Z, Jumaa, H, Melnick, A, Paietta, EM, Carroll, WL, Willman, CL, Lefebvre, V & Mus̈chen, M 2013, 'SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia', Blood, vol. 121, no. 1, pp. 148-155. https://doi.org/10.1182/blood-2012-05-428938
Ramezani-Rad P, Geng H, Hurtz C, Chan LN, Chen Z, Jumaa H et al. SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood. 2013 Jan 3;121(1):148-155. https://doi.org/10.1182/blood-2012-05-428938
Ramezani-Rad, Parham ; Geng, Huimin ; Hurtz, Christian ; Chan, Lai N. ; Chen, Zhengshan ; Jumaa, Hassan ; Melnick, Ari ; Paietta, Elisabeth M. ; Carroll, William L. ; Willman, Cheryl L. ; Lefebvre, Véronique ; Mus̈chen, Markus. / SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. In: Blood. 2013 ; Vol. 121, No. 1. pp. 148-155.
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