EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency

Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency

Diagnostic challenges in a child with early onset desmoplastic medulloblastoma and homozygous variants in MSH2 and MSH6

International audienceConstitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer susceptibility syndrome caused by biallelic germline mutations in one of the mismatch repair (MMR

Loss of Pax5 exploits sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL

Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL–negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/− mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.J. Hauer has been supported by the German Cancer Aid (Project 110997 and Translational Oncology Program 70112951), the German Jose Carreras Foundation (DJCLS 02R/2016), the Kinderkrebsstiftung (2016/17), and the "Elterninitiative Kinderkrebstiftung e.V." S. Ginzel has been supported by a scholarship of the Hochschule Bonn-Rhein-Sieg. M. Muschen is an HHMI Faculty Scholar (HHMI- € 55108547) and supported by NIH/NCI through an Outstanding Investigator Award (R35CA197628, R01CA137060, R01CA157644, R01CA172558, R01CA213138) to M. Muschen, a Wellcome Trust Senior Investigator Award, € the Leukemia and Lymphoma Society, the Norman and Sadie Lee Foundation (for Pediatric Cancer, to M. Muschen), and the Dr. Ralph and Marian € Falk Medical Research Trust (to M. Muschen), Cancer Research Institute € through a Clinic and Laboratory Integration Program grant (to M. Muschen) € and the California Institute for Regenerative Medicine (CIRM) through DISC2-10061. A. Borkhardt has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in I. Sanchez-García's group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R, and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y Leon (BIO/SA51/15, CSI001U14, UIC-017, and CSI001U16), Fundacion Inocente Inocente and by the ARIMMORA project [European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282891]. I. Sanchez-García's lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A. Borkhardt and I. Sanchez-García have been supported by the German Carreras Foundation (DJCLS R13/26). Research in C. Vicente-Duenas's ~ group is partially supported by FEDER, Ministerio de Economía y Competitividad ("Miguel Servet" Grant - CP14/00082 - AES 2013-2016) and (PI17/00167) from the Instituto de Salud Carlos III. A. Martín-Lorenzo and G. Rodríguez-Hernandez were supported by FSE-Conserjería de Educacion de la Junta de Castilla y Leon (CSI001-13 and CSI001-15, respectively). F. Auer was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship (AU 525/1-1)

Runtime Prediction von Textmining-Applikationen im Grid am Beispiel von ProMiner

Grid Infrastrukturen sind heute in der Lage, auch große Datenmengen verteilt zu verarbeiten. Ein Anwendungsgebiet, das davon profitiert, ist das Textmining. Es zeichnet sich vor allem durch die große Anzahl voneinander unabhängiger Teiljobs aus, in die eine Aufgabe zerlegt werden kann. Um die Gesamtlaufzeit bis zur Fertigstellung eines Textmininglaufes für einen großen Datenbestand zu optimieren, ist Load-Balancing unerlässlich. Dafür muss abgeschätzt werden, wie lange eine Ressource für die Lösung eines Teilproblems benötigt. Diese Abschätzungen beruhen auf den Aufzeichnungen vorangegangener Textminingverarbeitungen. Sind darüber noch keine Daten vorhanden, muss die Laufzeitvorhersage anhand der Leistungsfähigkeit der Hardware einer Ressource prognostiziert werden. Wir stellen in dieser Arbeit Methoden vor, mit denen die Laufzeit für Textmining-Applikationen mittels historischer Daten und Hardwareeigenschaften vorhergesagt werden kann. Dabei nutzen wir Methoden der Statistik und des maschinellen Lernens, um eine Prognose zu berechnen. Anschließend wird ein Dienst vorgestellt, der eine Laufzeitvorhersage im Grid anbietet. Er kann auch für andere Anwendungsgebiete als das Textmining eingesetzt werden und ist in der Lage, Informationen über die Laufzeiten von Jobs auf den Ressourcen abzurufen. Dazu nutzt er bereits vorhandene Dienste der Grid-Middleware und kann sich so dynamisch in bestehende Strukturen eingliedern

Enabling Versatile And Comprehensive Analysis Of Genomic Variant Data

The initially large number of variants is reduced by applying custom variant annotation and filtering procedures. This requires complex software toolchains to be set up and data sources to be integrated. Furthermore, increasing study sizes subsequently require higher efforts to manage datasets in a multi-user and multi-institution environment. It is common practice to expect numerous iterations of continuative respecification and refinement of filter strategies, when the cause for a disease or phenotype is unknown. Data analysis support during this phase is fundamental, because handling the large volume of data is not possible or inadequate for users with limited computer literacy. Constant feedback and communication is necessary when filter parameters are adjusted or the study grows with additional samples. Consequently, variant filtering and interpretation becomes time-consuming and hinders a dynamic and explorative data analysis by experts.Die Next Generation Sequenzierung (NGS) identifiziert hunderttausende Mutationen pro Individuum und eröffnet der Forschung und medizinischen Behandlung neue Erkenntnisse. Dies führte zur verbesserten Charakterisierung von Tumoren, der Entdeckung neuer krankheitsverursachender Mechanismen bei genetischen Erkrankungen sowie der Identifizierung neuer Behandlungsmöglichkeiten. Sequenzierungexperimente sind multidisziplinäre Projekte, die die Fachkenntnisse unterschiedlicher Experten benötigen, um Daten zu generieren und zu verarbeiten. Die Ergebnisse werden von Genomikern (z.B. Molekularbiologen und Mediziner) interpretiert, um signifikante Varianten in einem Heuhaufen von Mutationen zu finden

Identification of TEL-AML1 (ETV6-RUNX1) associated DNA and its impact on mRNA and protein output using ChIP, mRNA expression arrays and SILAC

The contribution of the most common reciprocal translocation in childhood B-cell precursor leukemia t(12;21)(p13;q22) to leukemia development is still under debate. Direct as well as secondary indirect effects of the TEL-AML1 fusion protein are commonly recorded by using cell lines and patient samples, often bearing the TEL-AML1 fusion protein for decades. To identify direct targets of the fusion protein a short-term induction of TEL-AML1 is needed. We here describe in detail the experimental procedure, quality controls and contents of the ChIP, mRNA expression and SILAC datasets associated with the study published by Linka and colleagues in the Blood Cancer Journal [1] utilizing a short term induction of TEL-AML1 in an inducible precursor B-cell line model

Whole-genome paired-end analysis confirms remarkable genomic stability of atypical teratoid/rhabdoid tumors

Hoell JI, Gombert M, Bartenhagen C, et al. Whole-genome paired-end analysis confirms remarkable genomic stability of atypical teratoid/rhabdoid tumors. Genes, chromosomes & cancer. 2013;52(10):983-985