PAX5 overexpression is not enough to reestablish the mature B-cell phenotype in classical Hodgkin lymphoma

Dimitrova, Lora; Seitz, Volkhard; Hecht, J; Lenze, Dido; Hansen, Per Boye; Szczepanowski, Monika; Ma, Liya; Oker, Elisabeth; Sommerfeld, Anke; Jundt, Franziska; Klapper, Wolfram; Hummel, Michael

doi:10.1038/leu.2013.211

Cited by 24 publications

(22 citation statements)

References 14 publications

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“…This notion is further supported by recent data showing that introduction of PAX5 into Hodgkin lymphoma cells is unable to reestablish a mature B-cell expression signature (51).…”

Section: Discussionsupporting

confidence: 73%

Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development

Fortschegger

Anderl

Denk

et al. 2014

Molecular Cancer Research

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PAX5, a transcription factor pivotal for B-cell commitment and maintenance, is one of the most frequent targets of somatic mutations in B-cell precursor acute lymphoblastic leukemia. A number of PAX5 rearrangements result in the expression of in-frame fusion genes encoding chimeric proteins, which at the N-terminus consistently retain the PAX5 DNA-binding paired domain fused to the C-terminal domains of a markedly heterogeneous group of fusion partners. PAX5 fusion proteins are thought to function as aberrant transcription factors, which antagonize wild-type PAX5 activity. To gain mechanistic insight into the role of PAX5 fusion proteins in leukemogenesis, the biochemical and functional properties of uncharacterized fusions: PAX5-DACH1, PAX5-DACH2, PAX5-ETV6, PAX5-HIPK1, and PAX5-POM121 were ascertained. Independent of the subcellular distribution of the wild-type partner proteins, ectopic expression of all PAX5 fusion proteins showed a predominant nuclear localization, and by chromatin immunoprecipitation all of the chimeric proteins exhibited binding to endogenous PAX5 target sequences. Furthermore, consistent with the presence of potential oligomerization motifs provided by the partner proteins, the self-interaction capability of several fusion proteins was confirmed. Remarkably, a subset of the PAX5 fusion proteins conferred CD79A promoter activity; however, in contrast with wild-type PAX5, the fusion proteins were unable to induce Cd79a transcription in a murine plasmacytoma cell line. These data show that leukemia-associated PAX5 fusion proteins share some dominating characteristics such as nuclear localization and DNA binding but also show distinctive features.Implications: This comparative study of multiple PAX5 fusion proteins demonstrates both common and unique properties, which likely dictate their function and impact on leukemia development.

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“…This notion is further supported by recent data showing that introduction of PAX5 into Hodgkin lymphoma cells is unable to reestablish a mature B-cell expression signature (51).…”

Section: Discussionsupporting

confidence: 73%

Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development

Fortschegger

Anderl

Denk

et al. 2014

Molecular Cancer Research

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“…Second, PAX5, a transcription factor critical for B-cell commitment, is often moderately expressed in HRS cells irrespective of their lost B-cell phenotype 31 but virtually undetectable in cHL cell lines KM-H2 and L428 (supplemental Figure 3A). To rule out that subcritical PAX5 expression may hinder reconstitution of CD19 promoter activity, we infected L428 cells prior to the pharmacological screening with a mifepristone-inducible construct encoding PAX5 24 (supplemental Figure 3B). …”

Section: Resultsmentioning

confidence: 99%

“…23,24 Plasmids encoding B-cell-specific promoter sequences and a geneticin (G418) resistance gene were generous gifts from C. Tonnelle (EmMar-CD19-pTRIP) and M. Sigvardsson (pGL3-mb-1 [CD79a] and pGL3-B29 [CD79b]). [25][26][27] The EmMar-CD19 fragment was further subcloned into the luciferase-encoding pGL3 reporter vector system as well.…”

Section: Plasmid Constructionmentioning

confidence: 99%

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma

Neuenschwander

et al. 2017

Blood

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Key Points• A pharmacological screening identified compounds that reactivate B-cell-specific gene expression in cHL cell lines.• B-cell phenotype-restoring drug combinations render cHL cell lines susceptible to B-NHL-reminiscent targeted therapies.Classical Hodgkin lymphoma (cHL), although originating from B cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but it may also render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted a high-throughput pharmacological screening based on >28 000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote reexpression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of 2 of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the antileukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked reexpression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibodymediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell non-Hodgkin lymphoma-tailored small-compound inhibitors ibrutinib and idelalisib. In essence, we report here a conceptually novel, redifferentiation-based treatment strategy for cHL. (Blood. 2017;129(1):71-81)

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“…The most related previous works on secure kNN queries are [8,14,15,28,31,34,36,37]. Wong et al [34] proposed a new encryption scheme called asymmetric scalar-product-preserving encryption In their work, data and query are encrypted using slightly different encryption schemes before being outsourced to the cloud server and all the clients know the private key.…”

Section: Secure Knn Queriesmentioning

confidence: 99%

“…Instead of asking the cloud server to retrieve the exact kNN result, their method retrieves a relevant encrypted partition E(R) for E(Q) such that R is guaranteed to contain the kNN of Yi et al [37] propose solutions for secure kNN queries based on oblivious transfer paradigm. Qi et al [31] proposed efficient protocols with linear computation and communication complexity for secure kNN queries, when the data is distributed between two parties who want to cooperatively compute the answers without revealing to each other their private data. Qi et al [31] proposed efficient protocols with linear computation and communication complexity for secure kNN queries, when the data is distributed between two parties who want to cooperatively compute the answers without revealing to each other their private data.…”

Section: Secure Knn Queriesmentioning

confidence: 99%

Biomedical Data Management and Graph Online Querying

Wang¹,

Luo²,

Weng³

et al. 2016

Lecture Notes in Computer Science

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Abstract. Algorithm evaluation provides a means to characterize variability across image analysis algorithms, validate algorithms by comparison of multiple results, and facilitate algorithm sensitivity studies. The sizes of images and analysis results in pathology image analysis pose significant challenges in algorithm evaluation. We present SparkGIS, a distributed, in-memory spatial data processing framework to query, retrieve, and compare large volumes of analytical image result data for algorithm evaluation. Our approach combines the in-memory distributed processing capabilities of Apache Spark and the efficient spatial query processing of Hadoop-GIS. The experimental evaluation of SparkGIS for heatmap computations used to compare nucleus segmentation results from multiple images and analysis runs shows that SparkGIS is efficient and scalable, enabling algorithm evaluation and algorithm sensitivity studies on large datasets.

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PAX5 overexpression is not enough to reestablish the mature B-cell phenotype in classical Hodgkin lymphoma

Cited by 24 publications

References 14 publications

Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development

Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma

Biomedical Data Management and Graph Online Querying

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