Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma

Jundt, Franziska; Açıkgöz, Özgür; Kwon, Sun-Ho; Schwarzer, Rolf; Anagnostopoulos, Ioannis; Wiesner, Burkhard; Mathas, Stephan; Hummel, Michael; Stein, Harald; Hm, Reichardt; Dörken, Bernd

doi:10.1038/leu.2008.101

Cited by 72 publications

(88 citation statements)

References 42 publications

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“…Our previous data demonstrated that the E2A antagonist ABF-1 is overexpressed in HRS cells, and we identified ABF-1 as a Notch1-specific target gene using siRNA against Notch1. 5,23 ABF-1 and/or HEY1 were 5 Our data indicate that Notch signaling is constitutively active in HRS cells and is efficiently blocked by GSI XII.…”

Section: Notch Inhibition Controls the Survival Of Hrs Cellsmentioning

confidence: 72%

“…5 Reverse transcription-PCR analysis was performed as described using primers and probes for human HEY1, ABF-1, CCR7, c-IAP2. 5 As an internal control human b-actin was amplified. Primer sequences are available upon request.…”

Section: Rna Preparation Semi-quantitative and Quantitative Reverse mentioning

confidence: 99%

“…5 Therefore, aberrant expression of this master regulator of T-cell development may contribute to loss of the B cell phenotype and expression of T-cell-specific genes in classical Hodgkin lymphoma (cHL). 5 Despite abundant evidence for a complex context-dependent cross talk between Notch1 and nuclear factor-kB (NF-kB) signaling in hematopoietic cells, 6 it remains elusive whether aberrant Notch activity interferes with the major pathogenetic mechanism in cHL: constitutive activation of the NF-kB signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

“…4 We further demonstrated that absence of the main Notch1 inhibitor Deltex1 and high-level expression of the Notch co-activator of the Mastermind-like family contribute to deregulated Notch signaling in HRS cells. 4,5 Notch1 activity reduces the expression of the B cell transcription factors E12 and E47, and EBF1 and induces the transcription of activated B cell factor 1 (ABF-1). 5 In addition, Notch1 binds to PAX5 in HRS cells, which might impair PAX5 function.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 Notch1 activity reduces the expression of the B cell transcription factors E12 and E47, and EBF1 and induces the transcription of activated B cell factor 1 (ABF-1). 5 In addition, Notch1 binds to PAX5 in HRS cells, which might impair PAX5 function. 5 Therefore, aberrant expression of this master regulator of T-cell development may contribute to loss of the B cell phenotype and expression of T-cell-specific genes in classical Hodgkin lymphoma (cHL).…”

Section: Introductionmentioning

confidence: 99%

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Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

2011

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A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-jB (NF-jB) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed-Sternberg (HRS) cells. Despite abundant evidence for a complex contextdependent cross talk between Notch and NF-jB signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the c-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-jB signaling, interfering with processing of the NF-jB2 gene product p100 into its active form p52. As a result, expression of Notch and NF-jB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-jB signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-jB signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL.

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Section: Notch Inhibition Controls the Survival Of Hrs Cellsmentioning

confidence: 72%

Section: Rna Preparation Semi-quantitative and Quantitative Reverse mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

2011

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Modulation of PKC‐α promotes lineage reprogramming of committed B lymphocytes

et al. 2012

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IntroductionCommitment of hematopoietic stem cells (HSCs) toward the Blymphocyte lineage is tightly controlled by a myriad of transcription factors, including E26 transformation-specific family factor, PU.1, basic helix-loop-helix family factor, E2A (encodes E12 and E47 proteins), early B-cell factor (EBF), and paired box gene 5 (Pax5) [1]. These proteins initiate a differentiation program [4,5], establishing that Pax5 expression is essential to maintain the cell identity of the B-cell lineage.Disruption of the expression or function of transcription factors may account for the occurrence of lineage switching during malignancies. Indeed, deletion of Pax5 from mature B cells in mice leads to the development of aggressive progenitor lymphomas that are indistinguishable from Pax5 −/− pro-B cells, except that they possess rearranged heavy and light chain gene loci [4,5]. Recent studies have indicated that Pax5 is mutated or targeted for chromosomal translocation in a number of human B-cell malignancies underlining the importance of establishing that proteins are responsible for regulating Pax5 function [7,8].Protein kinase C (PKC) represents a family of serine/threonine protein kinases that are essential for regulation of proliferation, apoptosis, differentiation, and migration in normal cells [9,10]. Isoforms comprising the mammalian PKC family share a common catalytic domain, and are classified based on their regulatory domain structure, which dictates cofactor dependence for activation: classical cPKCs (α, βI, βII, γ) are activated by phospholipids, diacylglycerol (DAG), and Ca 2+ ; novel nPKCs (δ, ε, η, θ)by phospholipids and DAG, but not Ca 2+ ; and atypical aPKCs (ζ, ι/λ) are activated independently of Ca 2+ and DAG [11,12].Early studies utilizing the DAG analogues, phorbol esters, to modulate PKC activity in transformed cells suggested that PKC behaves as a rheostat for cell fate decision: no/low activity enabling cells to maintain a progenitor state; moderate activity resulting in the adoption of a myeloid lineage; and high PKC activation leading to eosinophil lineage commitment [13][14][15]. Although these experiments were insufficient to define a clear role for PKC in modulating lineage decisions, due to the ability of phorbol esters to regulate DAG-binding proteins such as , additional studies showed that PKC-α specifically influences the ability of human bone marrow (BM) cells to differentiate toward erythroid lineage cells [13]. This suggests that the PKC family plays a role in cell fate decisions. During the course of our studies assessing the role of the PKC family in early development of B lymphocytes, we established that expression of a dominant negative PKC-α K 368 R (PKC-α-KR) construct in HSC-enriched populations resulted in the outgrowth of transformed B-lineage cells that resemble chronic lymphocytic leukemia (CLL) [17]. Closer analysis reveals that PKC-α-KR expression can also provoke lineage plasticity in B-committed precursors, enabling CD19 + cells to differentiate toward the myeloid and N...

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Deregulated FOX genes in Hodgkin lymphoma

Nagel

Meyer

Kaufmann

et al. 2014

Genes Chromosomes & Cancer

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FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFβ- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets.

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Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma

Cited by 72 publications

References 42 publications

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

Modulation of PKC‐α promotes lineage reprogramming of committed B lymphocytes

Deregulated FOX genes in Hodgkin lymphoma

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