IG-MYC rearrangement defines a high-risk subgroup of B-cell precursor acute lymphoblastic leukaemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE174248 | GEO | 2022/05/31
REPOSITORIES: GEO
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Project description:IG-MYC rearrangement defines a high-risk subgroup of B-cell precursor acute lymphoblastic leukaemia
| PRJNA728958 | ENA
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.
| EGAS00001005111 | EGA
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.
2018-10-08 | GSE114210 | GEO
Project description:By whole-genome, exome, transcriptome and methylome sequencing of four proto-typical Burkitt lymphomas (BL) with IG-MYC translocation we identified seven recurrently mutated genes including ID3. In an extended cohort, 36/53 (68%) molecularly-defined BL carried potentially damaging mutations of ID3 which were enriched at somatic hypermutation motifs. Only 6/47 (13%) other IG-MYC-positive B-cell lymphomas carried ID3 mutations suggesting cooperation of ID3 inactivation and IG-MYC translocation to be a hallmark of Burkitt lymphomagenesis.
| EGAS00001000271 | EGA
Project description:IG-MYC-positive neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas
| PRJNA470587 | ENA
Project description:The Journal of Experimental Medicine, Volume 194, Number 11, December 3, 2001 1639-1648 Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia Andreas Rosenwald1, Ash A. Alizadeh2, George Widhopf5, Richard Simon6, R. Eric Davis1, Xin Yu1, Liming Yang1, Oxana K. Pickeral1, Laura Z. Rassenti5, John Powell7, David Botstein3, John C. Byrd8, Michael R. Grever9, Bruce D. Cheson10, Nicholas Chiorazzi11, Wyndham H. Wilson12, Thomas J. Kipps5, Patrick O. Brown2,4 and Louis M. Staudt1 The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression "signature," irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.
2005-06-29 | E-SMDB-1002 | biostudies-arrayexpress
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.
2023-03-11 | PXD032980 | Pride
Project description:We analyzed the transcriptome (RNA-seq) of mouse plasma cells (PC) expressing a human Ig light chain from a patient suffering light chain deposition disease (LCDD) as compared to control plasma cells (WT and DH-LMP2A, the latter producing no complete immunoglobulins, only free Ig light chains). Ig light chains causing LCDD present structural peculiarities leading to their aggregation and deposition into tissues and organs, mainly the kidney. We sought to determine if plasma cells producing these abnormal Ig could present specific phenotypes. The aim of the present study is to analyse the transcriptomic signature of plasma cells producing abnormal Ig free light chains.
2020-05-14 | GSE119048 | GEO
Project description:During activation, T cells integrate multiple signals from APCs and cytokine milieu. The blockade of these signals can have clinical benefits as exemplified by CTLA4-Ig, which blocks interaction of B7 co-stimulatory molecules on APCs with CD28 on T cells. Variants of CTLA4-Ig, abatacept and belatacept are FDA approved as immunosuppressive agents in arthritis and transplantation whereas murine studies suggested that CTLA4-Ig can be beneficial in a number of other diseases. However, detailed analysis of human CD4 cell hyporesponsivness induced by CTLA4-Ig has not been performed. Herein, we established a model to study effect of CTLA4-Ig on the activation of human naïve T cells in a human mixed lymphocytes system. Comparison of human CD4 cells activated in the presence or absence of CTLA4-Ig, showed that co-stimulation blockade during TCR activation does not affect NFAT signaling but results in decreased activation of NF-kB and AP-1 transcription factors followed by profound decrease in proliferation and cytokine production. The resulting T cells become hyporesponsive to secondary activation and, although capable of receiving TCR signals, fail to proliferate or produce cytokines, demonstrating properties of anergic cells. However, unlike some models of T cell anergy, these cells did not possess increased levels of TCR signaling inhibitor CBLB. Rather, the CTLA4-Ig induced hyporesponsiveness was associated with an elevated level of p27kip1 cyclin-dependent kinase inhibitor.
2015-02-17 | GSE64712 | GEO
Project description:During activation, T cells integrate multiple signals from APCs and cytokine milieu. The blockade of these signals can have clinical benefits as exemplified by CTLA4-Ig, which blocks interaction of B7 co-stimulatory molecules on APCs with CD28 on T cells. Variants of CTLA4-Ig, abatacept and belatacept are FDA approved as immunosuppressive agents in arthritis and transplantation whereas murine studies suggested that CTLA4-Ig can be beneficial in a number of other diseases. However, detailed analysis of human CD4 cell hyporesponsivness induced by CTLA4-Ig has not been performed. Herein, we established a model to study effect of CTLA4-Ig on the activation of human naM-CM-/ve T cells in a human mixed lymphocytes system. Comparison of human CD4 cells activated in the presence or absence of CTLA4-Ig, showed that co-stimulation blockade during TCR activation does not affect NFAT signaling but results in decreased activation of NF-kB and AP-1 transcription factors followed by profound decrease in proliferation and cytokine production. The resulting T cells become hyporesponsive to secondary activation and, although capable of receiving TCR signals, fail to proliferate or produce cytokines, demonstrating properties of anergic cells. However, unlike some models of T cell anergy, these cells did not possess increased levels of TCR signaling inhibitor CBLB. Rather, the CTLA4-Ig induced hyporesponsiveness was associated with an elevated level of p27kip1 cyclin-dependent kinase inhibitor. Time series. Human resting and activated T cell dUTP mRNA-Seq profiles were generated on Illumina HiSeq2500
2015-02-17 | E-GEOD-64712 | biostudies-arrayexpress