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IG-MYC rearrangement defines a high-risk subgroup of B-cell precursor acute lymphoblastic leukaemia

ABSTRACT: 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 Ã¢Â€Âœdouble-hitÃ¢Â€Â 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.

PROVIDER: EGAS00001005111 | EGA |

REPOSITORIES: EGA

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Project description:MYC translocations are the biologic hallmark of Burkitt lymphomas but also occur in other mature B-cell lymphomas. If accompanied by chromosomal breaks targeting the BCL2 and/or BCL6 oncogenes, these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas (DHLs); otherwise, the term single-hit lymphoma (SHL) is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphomas, we explored, after exclusion of molecular Burkitt lymphoma (mBL) as defined by gene expression profiling (GEP), the molecular, pathological and clinical aspects of 80 MYC translocation (MYC+) lymphomas (31 SHL, 26 BCL2+/MYC+, 14 BCL6+/MYC+, 6 BCL2+/BCL6+/MYC+ and 3 MYC+ lymphomas with unknown BCL6 status). Comparison of SHL and DHL revealed no difference in frequency of MYC partner (IG/non-IG), genomic complexity or MYC expression and no differences in GEP. DHL showed a more frequent GCB-like GEP and higher IGH and MYC mutation rates. GEP revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ DHL. BCL2+/MYC+ DHL showed a more frequent GCB-like GEP. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In contrast to mBL and lymphomas without MYC break, SHL and DHL patients had similar poor outcome. Our data suggest that after excluding mBL, MYC+ lymphomas could be biologically widely lumped without further need for subclassification. 32 diffuse large B-cell lymphoma samples were hybridized to HG-U133A Affymetrix GeneChips. In addition, this study contains 30 already published samples, which contribute to GSE4475 (Hummel et al. 2006 (PMID 16760442)), as well as 18 already published samples from GSE22470 (Salaverria et al. 2011 (PMID 21487109)). No re-normalisation of the published samples was performed. The complete dataset representing: (1) the 32 diffuse large B-cell lymphoma Samples, (2) the 30 Samples from GSE4475 and (3) the 18 Samples from GSE22470, is linked below as a supplementary file

Project description:For sporadic Burkitt lymphoma (BL) few genetic lesions are known besides the pathognomonic IG-MYC translocations. Thirtynine molecularly-defined BL were analyzed with high-resolution single-nucleotide polymorphism chips for genomic imbalances and uniparental disomy (UPD). Imbalances were correlated to transcript profiling and selected miRNA analysis. Translocations affecting the MYC locus were studied by fluoresence in situ hybridization. We detected 528 copy number changes, defining 29 recurrently imbalanced regions. 518 regions of UPD were found, but these were rarely recurrent. Combined imbalance mapping and transcript profiling revealed a profound correlation between copy number and expression. Several recurrent imbalances affected the MYC pathway: The miRNA-supercluster 17-92 was frequently gained and the transcription factor E2F2 was recurrently deleted. Molecular BL lacking MYC translocations showed MYC gains. Amplifications of the polymerase iota gene were associated with increased genomic instability. The present findings suggests that UPDs play no major role in the pathogenesis of BL, whereas some genes may contribute to BL development through gene dosage effects. Amplifications of the polymerase iota gene may be functionally linked with increased genomic instability in BL. The pattern and rarity of chromosomal changes detectable even at the high resolution employed here, together with aberrations of genes regulating MYC activity, support that deregulation of the MYC pathway is the major force driving BL pathogenesis, but show that this deregulation is more complex than previously known. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from whole tissue. Copy number and LOH analysis of 500K SNP arrays was performed for 30 molecularly-defined Burkitt lymphomas. Genotyping was performed using the BRLMM-algorithm. Only a single 250k Chip was performed for nine additional Burkitts. 20 normal references (10 of those hybridized to nsp-chips) extracted from healthy blood donors, used as normals in the analysis in addition to the HapMap references provided by Affymetrix, are included in the set.

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IG-MYC rearrangement defines a high-risk subgroup of B-cell precursor acute lymphoblastic leukaemia

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