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The genomic landscape of pediatric T-cell acute lymphoblastic leukemia reveals novel X-linked somatic mutations associated with apoptosis resistance. [RNA-Seq]

ABSTRACT: Background. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis. It represents 15% of pediatric ALL and has a threefold higher incidence among males. T-cell transformation is a multi-step process involving cooperating events leading to altered T-cell signaling, proliferation, differentiation and survival. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Results. Using an integrative approach combining genomic and transcriptomic data, we performed comprehensive molecular characterization of 30 pediatric T-ALLs. We identified common T-ALL targets and confirmed the overall poor outcome of early immature cases. We also showed that deletion of the CDKN2A locus is associated with lower risk of relapse. In addition, we identified novel T-ALL drivers including a member of the spliceosome machinery U2AF1 as well as novel X-linked tumor suppressors MED12 and USP9X, that had never been associated to T-ALL before. Interestingly, almost 60% of these events were found in early immature cases which represented only 35% of the cohort. Functional validations further demonstrated the putative role of these novel T-ALL genes in driving transformation by demonstrating the aberrant splicing provoked by U2AF1 p.R35L and the protective effect against apoptosis of MED12 and USP9X repression. Conclusions. This study highlights the underlying genomic complexity of pediatric T-ALL, and the need for larger integrative studies to decipher the mechanisms that contribute to its various subtypes and provide opportunities to refine patient stratification and treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE78785 | GEO | 2016/03/02

SECONDARY ACCESSION(S): PRJNA313769

REPOSITORIES: GEO

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Project description:Background. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis. It represents 15% of pediatric ALL and has a threefold higher incidence among males. T-cell transformation is a multi-step process involving cooperating events leading to altered T-cell signaling, proliferation, differentiation and survival. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Results. Using an integrative approach combining genomic and transcriptomic data, we performed comprehensive molecular characterization of 30 pediatric T-ALLs. We identified common T-ALL targets and confirmed the overall poor outcome of early immature cases. We also showed that deletion of the CDKN2A locus is associated with lower risk of relapse. In addition, we identified novel T-ALL drivers including a member of the spliceosome machinery U2AF1 as well as novel X-linked tumor suppressors MED12 and USP9X, that had never been associated to T-ALL before. Interestingly, almost 60% of these events were found in early immature cases which represented only 35% of the cohort. Functional validations further demonstrated the putative role of these novel T-ALL genes in driving transformation by demonstrating the aberrant splicing provoked by U2AF1 p.R35L and the protective effect against apoptosis of MED12 and USP9X repression. Conclusions. This study highlights the underlying genomic complexity of pediatric T-ALL, and the need for larger integrative studies to decipher the mechanisms that contribute to its various subtypes and provide opportunities to refine patient stratification and treatment. Total RNA was extracted from bone marrow samples at diagnosis for patients 432, 437, 547, 693, 716, 743, 744, 748, 791 and 849 using the mirVana Isolation kit (Ambion) according to the manufacturerâs protocol. The Allprep DNA/RNA Mini kit (Qiagen) was used for relapse samples in patients 791 and 879. For patient 744, mature RNA was also purified using the Ambion's MicroPoly(A)Purist kit (Small Scale mRNA Purification Kit P/N AM1919). Following a DNAse I treatment, total or mature RNA samples were quantified by NanoDrop ND1000 (Thermo-Fisher Scientific) and RNA quality was assessed using the Agilent 2100 Bioanalyzer (Agilent). Ribosomal ribonucleic acid (rRNA) were depleted using the Invitrogen RiboMinus Eukaryote kit (Life Technologies). cDNA libraries were prepared using the SOLiD Total RNA-seq kit (diagnosis samples) and the Illumina TruSeq Stranded Total RNA kit (relapse samples) based on manufacturerâs protocol and sequenced on the Life Technologies SOLiD 5500 System or the Illumina HiSeq 2500 System.

Project description:Contemporary treatment of pediatric acute myeloid leukemia (AML) requires the assignment of patients to specific risk groups. To explore whether expression profiling of leukemic blasts could accurately distinguish between the known risk groups of AML, we analyzed 130 pediatric and 20 adult AML diagnostic bone marrow or peripheral blood samples using the Affymetrix U133A microarray. Class discriminating genes were identified for each of the major prognostic subtypes of pediatric AML, including t(15;17)[PML-RARalpha], t(8;21)[AML1-ETO], inv(16) [CBFbeta-MYH11], MLL chimeric fusion genes, and cases classified as FAB-M7. When subsets of these genes were used in supervised learning algorithms, an overall classification accuracy of more than 93% was achieved. Moreover, we were able to use the expression signatures generated from the pediatric samples to accurately classify adult de novo AMLs with the same genetic lesions. The class discriminating genes also provided novel insights into the molecular pathobiology of these leukemias. Finally, using a combined pediatric data set of 130 AMLs and 137 acute lymphoblastic leukemias, we identified an expression signature for cases with MLL chimeric fusion genes irrespective of lineage. Surprisingly, AMLs containing partial tandem duplications of MLL failed to cluster with MLL chimeric fusion gene cases, suggesting a significant difference in their underlying mechanism of transformation. All the gene expression arrays are available through http://www.stjuderesearch.org/site/data/AML1/ in the original study (PMID:15226186). To study the RAS gene expression in the human AML patients, a total of 104 AML cases with known KRAS and NRAS status (including 72 gene expression arrays in the original study and 32 additional arrays acquired later on), as well as 4 CD34+ normal bone marrow cases deposited in GEO GSE33315, were including in this depository. Gene expression profiling was performed on 104 single diagnosis tumor samples and 4 CD34+ normal bone marrow samples

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The genomic landscape of pediatric T-cell acute lymphoblastic leukemia reveals novel X-linked somatic mutations associated with apoptosis resistance. [RNA-Seq]

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