IG-MYC rearrangement defines a high-risk subgroup of B-cell precursor acute lymphoblastic leukaemia
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ABSTRACT:
PROVIDER: PRJNA728958 | ENA |
REPOSITORIES: ENA
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Project description:We assessed the molecular relationship of IG-MYC rearranged ALL with other ALL subtypes and Burkitt’s lymphoma and describe the genetic and clinical outcomes of IG-MYC rearranged ALL
2022-05-31 | GSE174248 | GEO
Project description:Translocations involving the immunoglobulin loci and the transcription factor MYC (IG-MYC) are seen in mature haematological malignancies, notably Burkitt lymphoma (BL). IG-MYC has also rarely been reported in phenotypically immature B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) where it presents a clinical management dilemma. This has historically resulted in inconsistent and suboptimal treatment, with enrolment onto clinical trials often prohibited.
To determine whether these patients, or what proportion of them, have BCP-ALL or BL, we conducted a detailed genetic and clinical outcome study. We observed the clonal and sub-clonal nature of this rearrangement, with copy number abnormalities of chromosome 1 (28/90, 31%) and rearrangements of BCL2/BCL6 (BCL2/6-r) (15/90, 16.6%) being the most frequent co-existent chromosomal abnormalities. Genomic sequencing identified precursor-like V(D)J region breakpoints and frequent mutations in genes implicated in BCP-ALL (KRAS, ASMTL and IKZF1). The methylome and transcriptome of patients determined two main features: (1) samples clustered according to established ALL cytogenetic features (KMT2A-r or IGH-DUX4); (2) samples with IG-MYC-r as the main cytogenetic finding formed a distinct cluster, separate from BL. The exception was cases with BCL2/6-r, which we propose represent a different disease, more akin to adult “double-hit†lymphomas.
When treated on historic ALL protocols, children with IG-MYC-r BCP-ALL had a 3 year EFS and OS rates of 47% and 60%, representing a high-risk disease. The underlying molecular features seen in most patients with IG-MYC rearrangements are strongly indicative of ALL suggesting there is no rationale to exclude them from standard or novel ALL therapies. Prospective enrolment onto risk-stratified clinical trials is critical to define and improve outcome in this high-risk group of BCP-ALL.
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Project description:We purified five subsets representing the main stages of human precursor-B-cell differentiation and CD34+lin- cord blood cells. The immunoglobulin (Ig) gene rearrangement status was determined using TaqMan quantitative PCR and GeneScan analysis. To gain more insight in the networks of genes that initiate and/or regulate the different types of Ig gene rearrangements, we analyzed their gene expression profiles by correlating the initiation of Ig gene rearrangements with specific upregulation of transcription factors. In addition to previously described transcription factors, we identified 16 candidate genes involved in initiation and/or regulation of Ig gene rearrangements.
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Project description:Genome wide DNA methylation profiling of Burkitt lymphoma subsets. The Illumina Infinium HumanMethylationEPIC BeadChip was used to obtain DNA methylation profiles across approximately 85,000 CpGs in B-cell lymphoma samples. Samples included 2 primary IG-MYC-positive B-cell neoplasms with precursor B-cell phenotype and 5 Burkitt lymphoma.
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Project description:Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) shown to have a dismal outcome on standard therapy. For improved diagnosis and prognosis of these patients, the initiating genetic events need to be elucidated. To investigate the genetic basis, the genomes of 94 iAMP21 patients were interrogated by genomic arrays, FISH and MLPA. Detailed mapping of chromosome 21 refined the common region of amplification (CRA) to 5.1 Mb; including the RUNX1 gene, miR-802 and genes mapping to the Down Syndrome Critical Region. Over a quarter of copy number alterations targeted chromosome 21, including telomeric deletions in 88% of patients. Global analysis by genomic arrays identified recurrent abnormalities affecting genes in key pathways. The frequency of these abnormalities were determined by FISH and/or MLPA; IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%) and RB1 (37%). Study of the clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 instability. This study provides convincing evidence that chromosome 21 instability is the only abnormality common to all iAMP21 patients and the initiating event is likely hidden within the complex structural rearrangements of this abnormal chromosome. DNA copy number analysis of 17 diagnostic and 1 relapse acute lymphoblastic leukaemia samples was performed using agilent 185K microarrays. These samples were hybridised against gender matched reference DNA.
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Project description:We report the DNA-methylation profiling of 10 regions selected from the DLK1-DIO3 domain on chromosome 14q32 in BM/PB samples from patients with acute promyelocytic leukaemia (APL), other subclasses of acute myeloid leukaemia and healthy donors, using high-throughput amplicon bisulfite sequencing with Roche 454 technology. We identify monoallelic-hypermethylation in APL only at the differentially methylated region (DMR) located upstream from the MEG3 gene (MEG3-DMR), whereas no changes in the DNA methylation profile were detected at the imprinting control region of the domain (IG-DMR) among the samples analysed. We show that the expression profile of 6 miRNAs clustered downstream from the MEG3-DMR correlates with the methylation profile at both DMRs. We demonstrate that miRNAs expression negatively correlates with DNA-methylation at the IG-DMR and MEG3 gene-body, whereas the correlation was positive for the CpGs located in the promoter of MEG3, including the binding sites for the insulator CTCF. We propose a loss of imprinting at the CTCF binding sites in patients with APL. These results are consistent with the previously reported DLK1-DIO3 miRNAs overexpression in APL, indicating a possible involvement of these ncRNAs in the pathogenesis of the disease. Investigation of the epigenetic regulation of the miRNAs clustered in 14q32 by next-generation sequencing
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Project description:We examined published microarray data from 104 acute lymphoblastic leukaemia patient specimens, that represent six different subgroups defined by cytogenetic features and immunophenotypes. Using the decision-tree based supervised learning algorithm Random Forest (RF), we determined a small set of genes for optimal subgroup distinction and subsequently validated their predictive power in an independent cohort of 68 specimens that were assessed using Affymetrix HG-U133A arrays.
2007-05-11 | E-TABM-125 | biostudies-arrayexpress
Project description:We report the DNA-methylation profiling of 10 regions selected from the DLK1-DIO3 domain on chromosome 14q32 in BM/PB samples from patients with acute promyelocytic leukaemia (APL), other subclasses of acute myeloid leukaemia and healthy donors, using high-throughput amplicon bisulfite sequencing with Roche 454 technology. We identify monoallelic-hypermethylation in APL only at the differentially methylated region (DMR) located upstream from the MEG3 gene (MEG3-DMR), whereas no changes in the DNA methylation profile were detected at the imprinting control region of the domain (IG-DMR) among the samples analysed. We show that the expression profile of 6 miRNAs clustered downstream from the MEG3-DMR correlates with the methylation profile at both DMRs. We demonstrate that miRNAs expression negatively correlates with DNA-methylation at the IG-DMR and MEG3 gene-body, whereas the correlation was positive for the CpGs located in the promoter of MEG3, including the binding sites for the insulator CTCF. We propose a loss of imprinting at the CTCF binding sites in patients with APL. These results are consistent with the previously reported DLK1-DIO3 miRNAs overexpression in APL, indicating a possible involvement of these ncRNAs in the pathogenesis of the disease.
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Project description:Acute myeloid leukemia (AML) is a disease with poor outcome but patients harbouring certain chromosomal rearrangements or complex karyotypes have particularly adverse prognosis. For these patients, targeted therapies have not yet made a significant clinical impact. To understand the molecular landscape of poor risk AML we profiled 55 poor risk AML patients using a multiomics approach that included transcriptomics (n=39), proteomics (n=55), phosphoproteomics (n=55) and an ex vivo drug sensitivity screening (482 compounds tested in at least 30 patients). We identified a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia, which we term MLLGA and MLLGB. MLLGA presented increased DOT1L phosphorylation, HOXA gene expression, CDK1 activity and phosphorylation of proteins involved in RNA metabolism, replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples. MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and IMPDH relative to other cases. The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia, suggesting a role of the nucleolar activity in sensitivity to IMPDH inhibition. In summary, our multilayer molecular profiling of poor risk AML matched to the response to hundreds of compounds identified a phosphoproteomics signature that define two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the development of specific therapies for KMT2A subgroups characterised by the MLLGA phosphoproteomics signature identified in this study.
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