title: SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Parham
authors.initials: P
authors.lastname: Ramezani-Rad
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.forename: Lai N
authors.initials: LN
authors.lastname: Chan
authors.forename: Zhengshan
authors.initials: Z
authors.lastname: Chen
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Véronique
authors.initials: V
authors.lastname: Lefebvre
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D019175:DNA Methylation; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011828:Radiation Chimera; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D055751:SOXC Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D014410:Tumor Stem Cell Assay
chemical_list: D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse; D000068877:Imatinib Mesylate