Aberrant expression and biological significance of Sox2, an embryonic stem cell transcriptional factor, in ALK-positive anaplastic large cell lymphoma

Gélébart, Pascal; Hegazy, Samar; Wang, P; Bone, Kathleen M.; Anand, Mona; Sharon, David; Hitt, Mary; Pearson, Joel D.; Ingham, Robert J.; Ma, Yupo; Lai, Raymond

doi:10.1038/bcj.2012.27

Cited by 36 publications

(52 citation statements)

References 51 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nearly all of NMCs are refractory to conventional chemotherapeutic regimens (2). Since SOX2 has been shown to confer chemotherapy resistance to cancer stem cells (19, 48–50), it is possible that the SOX2-associated sphere growth features contribute to the chemo-resistant nature of NMCs. It will be promising to further investigate this potential SOX2 function in NMC tumorigenesis and to determine if this could be an efficient therapeutic target for overcoming the NMC chemo-resistance.…”

Section: Discussionmentioning

confidence: 99%

Activation of SOX2 Expression by BRD4-NUT Oncogenic Fusion Drives Neoplastic Transformation in NUT Midline Carcinoma

et al. 2014

View full text Add to dashboard Cite

BRD4 is implicated in the pathogenesis of a number of different cancers. It is also the target of translocation t(15;19) that accounts for the highly aggressive NUT midline carcinoma (NMC). We discovered that t(15;19) NMC cells display the ability to grow into stem cell-like spheres and express an exceptionally high level of the stem cell marker, SOX2. The BRD4-NUT fusion oncogene resulting from t(15;19) translocation is required for the abnormal activation of SOX2, which drives the stem cell-like proliferation and cellular transformation in NMC cells. SOX2 knockdown phenocopies the effects of BRD4-NUT inhibition, whereas ectopic SOX2 expression rescues the phenotype. The BRD4-NUT induced abnormal SOX2 activation was observed in multiple NMC cell lines as well as in NMC primary tumors. We further demonstrate that BRD4-NUT oncoprotein recruits p300 to stimulate transcription activation, and that inhibition of p300 represses SOX2 transcription in NMC cells. These studies identify this stem cell marker as a novel BRD4-NUT target that supports the highly aggressive transforming activity of t(15;19) carcinomas. Our study provides new mechanistic insights for understanding how alteration of BRD4 function by BRD4-NUT oncogene leads to the highly malignant NMC carcinoma. Because abnormal stem cell self-renewal is frequently observed during tumor formation and metastasis, the aberrant stem cell-like proliferation associated with BRD4 dysregulation observed in NMC carcinoma may have implications for studying the oncogenic mechanism of other BRD4-associated tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of SOX2 Expression by BRD4-NUT Oncogenic Fusion Drives Neoplastic Transformation in NUT Midline Carcinoma

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The procedures of the xenograft studies were described previously. 20 Briefly, 5 3 10 6 Tet on-SupM2-STAT1C or Tet on-SupM2-empty vector (EV) cells growing exponentially were injected into the left or right flank of 4-week-old male mice. Two days later, the 8 mice were split into two groups (4 mice each) and fed with water containing 1 mg/mL sucrose and either 2 or 5 mg/ mL doxycycline.…”

Section: Scid Mouse Xenograft Studiesmentioning

confidence: 99%

STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma

Molavi

Zhang

et al. 2015

Blood

View full text Add to dashboard Cite

Key Points• Oncogenic tyrosine kinase NPM-ALK binds to and phosphorylates STAT1, thereby promoting its proteasome-/STAT3-dependent degradation.• STAT1 tumor suppressor effects in ALK1 ALCL include creating a STAT1/interferon-g loop and interfering with STAT3 transcriptional activities.The tumorigenicity of most cases of ALK-positive anaplastic large-cell lymphoma (ALK1 ALCL) is driven by the oncogenic fusion protein NPM-ALK in a STAT3-dependent manner.Because it has been shown that STAT3 can be inhibited by STAT1 in some experimental models, we hypothesized that the STAT1 signaling pathway is defective in ALK1 ALCL, thereby leaving the STAT3 signaling unchecked. Compared with normal T cells, ALK1 ALCL tumors consistently expressed a low level of STAT1. Inhibition of the ubiquitinproteasome pathway appreciably increased STAT1 expression in ALK1 ALCL cells. Furthermore, we found evidence that NPM-ALK binds to and phosphorylates STAT1, thereby promoting its proteasomal degradation in a STAT3-dependent manner. If restored, STAT1 is functionally intact in ALK1 ALCL cells, because it effectively upregulated interferon-g, induced apoptosis/cell-cycle arrest, potentiated the inhibitory effects of doxorubicin, and suppressed tumor growth in vivo. STAT1 interfered with the STAT3 signaling by decreasing STAT3 transcriptional activity/DNA binding and its homodimerization. The importance of the STAT1/STAT3 functional interaction was further highlighted by the observation that short interfering RNA knockdown of STAT1 significantly decreased apoptosis induced by STAT3 inhibition. Thus, STAT1 is a tumor suppressor in ALK1 ALCL. Phosphorylation and downregulation of STAT1 by NPM-ALK represent other mechanisms by which this oncogenic tyrosine kinase promotes tumorigenesis. (Blood. 2015;126(3):336-345) IntroductionSignal transducer and activator of transcription 1 (STAT1), a member of the STAT family of transcription factors and a major mediator of interferon-g (IFN-g), is known to carry tumor suppressor functions. [1][2][3] In comparison, STAT3, another STAT family member, is oncogenic when inappropriately activated. 4,5 Correlating with their opposing roles, STAT1 and STAT3 are known to have functional interactions. For instance, STAT1 and STAT3 can form heterodimers, 4,[6][7][8] and the expression of gene targets regulated by STAT1 and STAT3 is dependent on the relative proportions of STAT1 homodimers, STAT3 homodimers, and the STAT1/STAT3 heterodimers. 9,10 This concept is exemplified by the observation that treatment of multiple myeloma cell lines with interferon-a triggers a shift from STAT3 homodimers to STAT1 homodimers and STAT3/STAT1 heterodimers, and this biochemical change correlates with a switch from cell proliferation to apoptosis.10 Several other studies have also shown that STAT1 and STAT3 can directly antagonize each other functionally. [11][12][13][14][15] It has been reported that activated STAT3 suppresses the DNA binding of STAT1 homodimers in myeloid cells, although it does not affect STAT1 tyrosine phos...

show abstract

“…Recently, aberrant expression of Sox2 has been found in a relatively large number of cancer types, including breast cancer [7, 8], melanoma [9], and ALK + ALCL [10]. Sox2 expression in these cancers has been shown to correlate with cancer stemness properties, such as chemoresistance [11], tumor initiation [8, 9], and self-renewal [9].…”

Section: Introductionmentioning

confidence: 99%

A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma

Zhang

Gupta

et al. 2016

J Hematol Oncol

View full text Add to dashboard Cite

BackgroundWe have previously described the existence of two phenotypically distinct cell subsets in ALK-positive anaplastic large cell lymphoma (ALK + ALCL) based on their differential responsiveness to a Sox2 reporter (SRR2), with reporter-responsive (RR) cells being more tumorigenic and chemoresistant than reporter-unresponsive (RU) cells. However, the regulator(s) of RU/RR dichotomy are not identified. In this study, we aim to delineate the key regulator(s) of RU/RR dichotomy.MethodsJASPER motif match analysis was used to identify the putative factors binding to SRR2 sequence. SRR2 probe pull-down assay and quantitate real-time PCR were performed to analyze the regulation of Sox2 transcriptional activity by MYC. Methylcellulose colony formation assay, chemoresistance to doxorubicin and mouse xenograft study were performed to investigate the biological functions of MYC. PCR array and western blotting were executed to study related signaling pathways that regulate MYC expression. Immunofluorescence and immunohistochemistry assay were initiated to evaluate the expression of MYC and its correlation with its regulator by chi-square test analysis in human primary tumor cells.ResultsWe identified MYC as a potential regulator of RU/RR dichotomy. In support of its role, MYC was highly expressed in RR cells compared to RU cells, and inhibition of MYC substantially decreased the Sox2/SRR2 binding, Sox2 transcriptional activity, chemoresistance, and methylcellulose colony formation. In contrast, enforced expression of MYC in RU cells conferred the RR phenotype. The Wnt/β-catenin pathway, a positive regulator of MYC, was highly active in RR but not RU cells. While inhibition of this pathway in RR cells substantially decreased MYC expression and SRR2 reporter activity, experimental activation of this pathway led to the opposite effects in RU cells. Collectively, our results support a model in which a positive feedback loop involving Wnt/β-catenin/MYC and Sox2 contributes to the RR phenotype. In a mouse xenograft model, RU cells stably transfected with MYC showed upregulation of the Wnt/β-catenin/MYC/Sox2 axis and increased tumorigenecity. Correlating with these findings, there was a significant correlation between the expression of active β-catenin and MYC in ALK + ALCL primary tumor cells.ConclusionsA positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subset in ALK + ALCL.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0349-z) contains supplementary material, which is available to authorized users.

show abstract

Aberrant expression and biological significance of Sox2, an embryonic stem cell transcriptional factor, in ALK-positive anaplastic large cell lymphoma

Cited by 36 publications

References 51 publications

Activation of SOX2 Expression by BRD4-NUT Oncogenic Fusion Drives Neoplastic Transformation in NUT Midline Carcinoma

Activation of SOX2 Expression by BRD4-NUT Oncogenic Fusion Drives Neoplastic Transformation in NUT Midline Carcinoma

STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma

A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma

Contact Info

Product

Resources

About