ParMap, an Algorithm for the Identification of Complex Genomic Variations in Nextgen Sequencing Data

Next-generation sequencing produces high-throughput data, albeit with greater error and shorter reads than traditional Sanger sequencing methods. This complicates the detection of genomic variations, especially, small insertions and deletions. Here we describe ParMap, a statistical algorithm for the identification of complex genetic variants using partially mapped reads in nextgen sequencing data. We also report ParMap’s successful application to the mutation analysis of chromosome X exome-captured leukemia DNA samples

The molecular basis of T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T cell development, as result of a multistep oncogenic process involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Notably, these genetic alterations define distinct molecular groups of T-ALL with specific gene expression signatures and clinicobiological features. This review summarizes recent advances in our understanding of the molecular genetics of T-ALL

The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo

We used the opportunities afforded by the zebrafish to determine upstream pathways regulating mast cell development in vivo and identify their cellular origin. Colocalization studies demonstrated zebrafish notch receptor expression in cells expressing carboxypeptidase A5 (cpa5), a zebrafish mast cell-specific marker. Inhibition of the Notch pathway resulted in decreased cpa5 expression in mindbomb mutants and wild-type embryos treated with the γ-secretase inhibitor, Compound E.Aseries of morpholino knockdown studies specifically identified notch1b and gata2 as the critical factors regulating mast cell fate. Moreover, hsp70::GAL4;UAS::nicd1a transgenic embryos overexpressing an activated form of notch1, nicd1a, displayed increased cpa5, gata2, and pu.1 expression. This increase in cpa5 expression could be reversed and reduced below baseline levels in a dose-dependent manner usingCompound E. Finally, evidence that cpa5 expression colocalizes with lmo2 in the absence of hematopoietic stem cells revealed that definitive mast cells initially delineate from erythromyeloid progenitors. These studies identify a master role for Notch signaling in vertebrate mast cell development and establish developmental origins of this lineage. Moreover, these findings postulate targeting the Notch pathway as a therapeutic strategy in mast cell diseases. © 2012 by The American Society of Hematology

ChIP-on-chip significance analysis reveals ubiquitous transcription factor binding

ChIP-on-chip technology provides a genome-scale view of transcription factor (TF)/target interactions and a systems level window into transcriptional regulatory networks. However, while many studies have used ChIP-on-chip data to effectively discover new TF targets, statistical methods have fallen short of developing an accurate model to disassociate signals caused by experimental noise from those caused by true biological variation, thus leveraging the technology to provide high confidence predictions of the full range of interactions

CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to c-secretase inhibitors

Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with c-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to c-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs. Leukemia (2006) 20, 1279–1287. doi:10.1038/sj.leu.2404258; published online 11 May 200

ETV6 mutations in early immature human T cell leukemias

A substantial proportion of adult T-ALL samples display gene expression and mutation characteristics of both T cell and acute myeloid leukemias; mutations in ETV6 are found exclusively within this new molecular subgroup of adult T-ALL patients

ParMap, an algorithm for the identification of small genomic insertions and deletions in nextgen sequencing data

<p>Abstract</p> <p>Background</p> <p>Next-generation sequencing produces high-throughput data, albeit with greater error and shorter reads than traditional Sanger sequencing methods. This complicates the detection of genomic variations, especially, small insertions and deletions.</p> <p>Findings</p> <p>Here we describe ParMap, a statistical algorithm for the identification of complex genetic variants, such as small insertion and deletions, using partially mapped reads in nextgen sequencing data.</p> <p>Conclusions</p> <p>We report ParMap's successful application to the mutation analysis of chromosome X exome-captured leukemia DNA samples.</p

The BCL2A1 gene as a pre–T cell receptor–induced regulator of thymocyte survival

The pre–T cell receptor (TCR) is expressed early during T cell development and imposes a tight selection for differentiating T cell progenitors. Pre-TCR–expressing cells are selected to survive and differentiate further, whereas pre-TCR− cells are “negatively” selected to die. The mechanisms of pre-TCR–mediated survival are poorly understood. Here, we describe the induction of the antiapoptotic gene BCL2A1 (A1) as a potential mechanism regulating inhibition of pre–T cell death. We characterize in detail the signaling pathway involved in A1 induction and show that A1 expression can induce pre–T cell survival by inhibiting activation of caspase-3. Moreover, we show that in vitro “knockdown” of A1 expression can compromise survival even in the presence of a functional pre-TCR. Finally, we suggest that pre-TCR–induced A1 overexpression can contribute to T cell leukemia in both mice and humans