TITLE

Comprehensive Analysis of Transcriptome Variation Uncovers Known and Novel Driver Events in T-Cell Acute Lymphoblastic Leukemia

AUTHOR(S)
Kalender Atak, Zeynep; Gianfelici, Valentina; Hulselmans, Gert; De Keersmaecker, Kim; Devasia, Arun George; Geerdens, Ellen; Mentens, Nicole; Chiaretti, Sabina; Durinck, Kaat; Uyttebroeck, Anne; Vandenberghe, Peter; Wlodarska, Iwona; Cloos, Jacqueline; Foà, Robin; Speleman, Frank; Cools, Jan; Aerts, Stein
PUB. DATE
December 2013
SOURCE
PLoS Genetics;Dec2013, Vol. 9 Issue 12, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
RNA-seq is a promising technology to re-sequence protein coding genes for the identification of single nucleotide variants (SNV), while simultaneously obtaining information on structural variations and gene expression perturbations. We asked whether RNA-seq is suitable for the detection of driver mutations in T-cell acute lymphoblastic leukemia (T-ALL). These leukemias are caused by a combination of gene fusions, over-expression of transcription factors and cooperative point mutations in oncogenes and tumor suppressor genes. We analyzed 31 T-ALL patient samples and 18 T-ALL cell lines by high-coverage paired-end RNA-seq. First, we optimized the detection of SNVs in RNA-seq data by comparing the results with exome re-sequencing data. We identified known driver genes with recurrent protein altering variations, as well as several new candidates including H3F3A, PTK2B, and STAT5B. Next, we determined accurate gene expression levels from the RNA-seq data through normalizations and batch effect removal, and used these to classify patients into T-ALL subtypes. Finally, we detected gene fusions, of which several can explain the over-expression of key driver genes such as TLX1, PLAG1, LMO1, or NKX2-1; and others result in novel fusion transcripts encoding activated kinases (SSBP2-FER and TPM3-JAK2) or involving MLLT10. In conclusion, we present novel analysis pipelines for variant calling, variant filtering, and expression normalization on RNA-seq data, and successfully applied these for the detection of translocations, point mutations, INDELs, exon-skipping events, and expression perturbations in T-ALL.
ACCESSION #
93395212

 

Related Articles

  • Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia. Prima, V.; Gore, L.; Caires, A.; Boomer, T.; Yoshinari, M.; Imaizumi, M.; Varella-Garcia, M.; Hunger, S. P. // Leukemia (08876924);May2005, Vol. 19 Issue 5, p806 

    We analyzed the TS-2 acute lymphoblastic leukemia (ALL) cell line that contains a t(1;19)(q23;p13.3) but lacks E2A-PBX1 fusion typically present in leukemias with this translocation. We found that the t(1;19) in TS-2 fuses the 19p13 gene DAZAP1 (Deleted in Azoospermia-Associated Protein 1) to...

  • Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets. Lin, Y.-W.; Aplan, P. D. // Leukemia (08876924);Jun2007, Vol. 21 Issue 6, p1276 

    We compared the gene expression pattern of thymic tumors from precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) that arose in transgenic mice that overexpressed SCL, LMO1 or NUP98-HOXD13 (NHD13) with that of thymocytes from normal littermates. Only two genes, Ccl8 and Mrpl38, were...

  • NF-kappaB activation mediates resistance to IFN beta in MLL-rearranged acute lymphoblastic leukemia. Tracey, L.; Streck, C. J.; Du, Z.; Williams, R. F.; Pfeffer, L. M.; Nathwani, A. C.; Davidoff, A. M. // Leukemia (08876924);Apr2010, Vol. 24 Issue 4, p806 

    Acute lymphoblastic leukemia (ALL) harboring the t(4;11) translocation is associated with a very poor prognosis; innovative treatment strategies are required to improve the current 5-year survival rate of 30-40%. Interferon beta (IFN beta) has shown promise in the treatment of both solid and...

  • In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile. Pei, Deqing; Yang, Wenjian; Kager, Leo; Stocco, Gabriele; Cheng Cheng; Panetta, John C.; Ching-Hon Pui; Relling, Mary V.; Cheok, Meyling H.; Evans, William E. // PLoS Medicine;Apr2008, Vol. 5 Issue 4, pe83 

    William Evans and colleagues investigate the genomic determinants of methotrexate resistance and interpatient differences in methotrexate response in patients newly diagnosed with childhood acute lymphoblastic leukemia.

  • A breast mass and ALL. Tan, Winston; Tsai, Tsuong W. // Patient Care;8/30/2000, Vol. 34 Issue 16, p64 

    Presents a case of a 28-year-old woman with a mass in her right breast and additional complaints of shortness of breath and fatigue. Significance of the patient's medical history for the diagnosis of acute lymphocytic leukemia; Treatment.

  • Detection of PICALM-MLLT10 (CALM-AF10) and outcome in children with T-lineage acute lymphoblastic leukemia. Lo Nigro, L; Mirabile, E; Tumino, M; Caserta, C; Cazzaniga, G; Rizzari, C; Silvestri, D; Buldini, B; Barisone, E; Casale, F; Luciani, M; Locatelli, F; Messina, C; Micalizzi, C; Pession, A; Parasole, R; Santoro, N; Masera, G; Basso, G; Aricò, M // Leukemia (08876924);Dec2013, Vol. 27 Issue 12, p2419 

    A letter to the editor is presented that discusses detection of PICALM-MLLT10 in children with T-lineage acute lymphoblastic leukemia.

  • Acute Lymphoblastic Leukemia. Ching-Hon Pui // Encyclopedic Reference of Cancer;2001, p8 

    An encyclopedia entry for "acute lymphoblastic leukemia" (ALL) is presented. ALL is also known as acute lymphocytic leukemia and acute lymphoid leukemia. It is a malignant disease of immature T or B lymphocytes, or lymphoblasts. It arises from one or more genetic abnormality in a single...

  • Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias. Clappier, E.; Cuccuini, W.; Cayuela, J.-M.; Vecchione, D.; Baruchel, A.; Dombret, H.; Sigaux, F.; Soulier, J. // Leukemia (08876924);Jan2006, Vol. 20 Issue 1, p82 

    Strong expression of at least one of the three D-type cyclins is common in human cancers. While the cyclin D1 and D3 genes (CCND1 and CCND3) are recurrently involved in genomic rearrangements, especially in B-cell lymphoid neoplasias, no clear involvement of the cyclin D2 gene (CCND2) has been...

  • Stem Cell Hierarchy and Clonal Evolution in Acute Lymphoblastic Leukemia. Lang, Fabian; Wojcik, Bartosch; Rieger, Michael A. // Stem Cells International;7/6/2015, Vol. 2015, p1 

    Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission....

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics