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RNA sequencing of T-ALL (COG study)

ABSTRACT: The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure or relapse. We investigated 213 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL Studies 9404 and 0434 and identified a cluster cases characterized by increased expression of HOX9/10. In samples with >8-fold HOXA9/10 deregulation, the presence of specific molecular lesions were confirmed through a systematic review of cytogenetic databases, FISH and PCR testing. In cases with no identifiable lesions using the methods above, RNA sequencing was performed (Illumina and Ion Proton). Fifteen cases selected for RNA sequencing met three criteria: HOXA9/10 expression ≥8-fold above the median, sufficient RNA, and an incomplete or absent molecular explanation for each sample’s HOXA9/10 deregulation. Three cases were confirmed to have PICALM-AF10 fusions. Two additional AF10-R cases showed DDX3X-AF10 lesions, one of which harbored a novel CASK gene fragment in a complex CASK-DDX3X-AF10 translocation. Two cases harbored NUP98 fusions46 and one case each was identified for MLL-AF6, MLL-PICALM, HOXA10-(3’UTR)TRBC45, STAG2-LMO2, LOC338817-CCDC91. We could not identify fusion transcripts in 3 cases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71359 | GEO | 2017/06/29

SECONDARY ACCESSION(S): PRJNA291023

REPOSITORIES: GEO

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Microarray analyses of T-ALL (COG study)

Project description:The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure or relapse. We used the Affymetrix U133 Plus 2.0 chip to profile 100 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL AALL0434. We performed unsupervised hierarchical clustering of 25 HOXA probe sets within the cohort of 100 T-ALL cases. We identified a cluster of 20 cases (20%) characterized by increased expression of HOXA3, 5, 7, 9, and 10. In samples with HOXA9/10 deregulation, the presence of specific molecular lesions were confirmed through a systematic review of cytogenetic databases, FISH and PCR testing, and by RNA sequence analysis. Because MLL and AF10 genes rearrangements (MLL-R, AF10-R) are hallmarks of HOXA-deregulated leukemias, we sought to identify specific genes that are enriched with these genomic abnormalities.

2017-06-29 | GSE70536 | GEO

MLLT10 gene recombinations in pediatric T-Acute Lymphoblastic Leukemia

Project description:MLLT10, a 24 exons gene at 10p12, is known in leukemogenesis as partner of MLL or PICALM and recently NAP1L1. We identified HNRNPH1 and DDX3X, genes involved in RNA processing, as new MLLT10 partners in 2 cases of pediatric NOTCH1 positive T-ALL. HNRNPH1/5q35 encodes for a member of the ubiquitously expressed heterogeneous nuclear ribonucleoprotein (hnRNP) subfamily of RNA binding protein. DDX3X/Xp11.3, belongs to the big family of RNA helicases with a DEAD box domain. Whole genome analysis by SNPs and Combined Interphase FISH (CI-FISH) identified different co-operating lesions in the two cases. Fusion isoforms were found in both cases: interestingly all fusions retained the OM-LZ domain of MLLT10 that is needed to induce Acute Myeloid Leukemia in mice. Gene expression profiling (GEP) of the two new MLLT10 fusions was similar to PICALM-MLLT10 positive but differed from other HOXA positive T-ALL, suggesting MLLT10 fusions share a common leukemogenic pathway. Clinical data indicate relative good prognosis in T-ALL with MLLT10 variants. This submission represents the gene expression component of the study [For privacy reasons, SNP data will not be deposited].

2013-07-03 | E-GEOD-42765 | biostudies-arrayexpress

MLLT10 gene recombinations in pediatric T-Acute Lymphoblastic Leukemia

2013-07-03 | GSE42765 | GEO

EZH2 mutations can be detected in 23% of PICALM-MLLT10 (CALM-AF10) positive acute leukemias

Project description:Interest focuses on genes encoding histone demethylases in hematologic malignancies, such as EZH2 (enhancer of zeste homolog 2). EZH2 mutations were recurrently observed in lymphomas and chronic myeloid malignancies, but data in acute leukemias are limited. We investigated 13 PICALM-MLLT10 (=CALM-AF10) rearranged acute leukemia predominantly of T-lineage (7 m/6 f; 6–53 years) by deep-sequencing for EZH2mut and identified 3 (23%) EZH2mut carriers: one splice site mutation in exon 14, while two patients had missense mutations in the D1 region of exon 5 which interacts with different DNA methyltransferase genes (but no DNMT3Amut was detected in the 13 PICALM-MLLT10-positive patients). In contrast, no EZH2mut was found in an independent cohort of 12 PICALM-MLLT10-negative T-ALL. Gene expression profiling revealed increased expression of genes with a role for transcription or intracellular transport processes in the PICALM-MLLT10-positive cases. The frequent occurrence of EZH2mut in PICALM-MLLT10-positive malignancies emphasizes a cooperative effect in acute leukemias.

2011-11-25 | GSE30599 | GEO

EZH2 mutations can be detected in 23% of PICALM-MLLT10 (CALM-AF10) positive acute leukemias

2011-11-25 | E-GEOD-30599 | biostudies-arrayexpress

The quantitative analysis of transcriptomes derived from MLL-AF10 flox cells and MLL-AF10 (Tip60 flox/flox, Cre-ERT2) cells with or without the treatment of 4-OHT

Project description:Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region in frame to partner genes , and the resultant fusion proteins can cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as the HoxA cluster and Meis1, but the underlying mechanisms remain elusive. We found that the MLL-AF10 fusion recruits Tip60 to the Hoxa9 locus, where it acetylates H2A.Z, thereby promoting Hoxa9 expression. Following conditional deletion of Tip60, hypoacetylation of H2A.Z was accompanied by recruitment of Ezh2, the catalytic subunit of PRC2, suggesting that nucleosomes with hypoacetylated H2A.Z are the preferential targets of Ezh2. Our findings suggest that MLL-AF10 achieves active chromatin states by recruiting Tip60, which acetylates H2A.Z to prevent gene silencing by Ezh2.

2021-06-30 | GSE142558 | GEO

The genome-wide maps of H3K27me3 in MLL-AF10 (Tip60 flox/flox, Cre-ERT2) cells (MATIP cells) with or without the treatment of 4-OHT

2021-06-30 | GSE142557 | GEO

Peturbation of PICALM Levels Alters Cellular Cholesterol Metabolism

Project description:PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked Single Nucleotide Polymorphisms (SNPs) of PICALM to Alzheimer’s disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. GC-MS studies indicated that loss of PICALM increases total cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters cholesterol homeostasis via increased scavenging of cholesterol. Measurement of LDL receptor endocytosis further showed that PICALM deficient cells express higher LDLR levels resulting in higher lipoprotein internalization. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease.

2015-06-17 | GSE64855 | GEO

GeneChip Mapping 500K set and Genome-Wide Human SNP 6.0 Array for glioblastomas

Project description:High-density single nucleotide polymorphism (SNP) arrays were used to investigate genome-wide copy number (CN) alterations and loss of heterozygosity (LOH) in glioblastomas (GBM) patients; our aim focused on the identification and detailed characterization of the genetic alterations of the chromosomes altered in these tumors and the identification of subgroups of GBM with distinct cytogenetic patterns of alteration for the affected chromosomes potentially associated with the behavior of the disease. Overall, gains of chromosome 7, losses of chromosomes 9p and 10 were the most frequent chromosomal alterations. The 7p11.2 region was amplified in several cases. Based on CN alterations for chromosomes 7, 9 and 10, five different cytogenetic patterns with a significant impact on patient survival were identified; noteworthy, cases with EGFR amplification showed a better survival, specifically among patients older than 60 years. In addition, our results provide further evidence about the relevance of the EGFR, CDKN2A/B, MTAP genes, and other genes coded in chromosome 10 in the pathogenesis of GBM. Altogether, our results confirm the cytogenetic heterogeneity of GBM and suggest that stratification of these tumors into genetic subsets based on the combined assessment of cytogenetic alterations involving chromosomes 7, 9 and 10, may contribute to the prognostic evaluation of GBM.

2012-11-30 | GSE42631 | GEO

Assesment of gene expression upon AF10 deletion in MLL-AF9 secondary leukemia

Project description:Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Primary MLL-AF9 leukemias in the AF10 floxed background (homozygous) were transduced with MSCV-IRES-tdTomato (MIT) or the Cre recombinase expressing MIT vector, cells were sorted and injected into secondary recipient mice to generate Af10 floxed (MIT) or deleted (CRE) leukemias. BM cells fresly harvested from these leukemias were sorted for tdTomato expression and used for microarrays. BM cells from Hoxa9-Meis1 transduced primary leukemias were used for comparison.

2014-09-08 | E-GEOD-54499 | biostudies-arrayexpress

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