Somatic Mutations in Variant and IGHV4-34 Expressing Hairy Cell Leukemia
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ABSTRACT: To understand the genetic mechanisms driving variant and IGHV4-34 expressing hairy-cell leukemia, we performed whole exome sequencing of tumor/normal pairs from ten patients.
SECONDARY ACCESSION(S): PRJNA223180PRJNA223178
REPOSITORIES: dbGaP
Similar Datasets
Project description:<p>To understand the genetic mechanisms driving variant and IGHV4-34 expressing hairy-cell leukemia, we performed whole exome sequencing of tumor/normal pairs from ten patients.</p>
| phs000671.v1.p1 | EGA
Project description:Somatic mutations in variant and IGHV4-34 expressing hairy cell leukemia
| PRJNA223180 | ENA
Project description:Somatic mutations in variant and IGHV4-34 expressing hairy cell leukemia
| PRJNA223178 | ENA
Project description: Not available
| S-EPMC3693860 | biostudies-literature
Project description: Not available
| S-EPMC6849383 | biostudies-literature
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.
2016-03-02 | GSE78783 | GEO
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.
2016-03-02 | GSE78785 | GEO
Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia.
2019-04-05 | GSE127492 | GEO
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.
2016-03-02 | E-GEOD-78785 | biostudies-arrayexpress
Project description: Not available
| S-EPMC3668487 | biostudies-literature