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:The specificity of humoral immune responses depends on the functional rearrangement and expression of only one allele of immunoglobulin (Ig) genes. Here, we analyzed the comprehensive proteome of the murine Ig Emu enhancer, which governs the rearrangement and expression of the Ig mu heavy chain allele. By mass spectrometry of proteins bound at wild type versus mutant Emu enhancers, we identified Emu-binding proteins and associated multi-protein complexes. We found that the MSL/MOF complex, a regulator of gene dosage compensation in flies, binds Emu via transcription factor YY1 and facilitates Emu-driven chromatin looping and promoter interaction. Msl2 gene knockout in primary pre-B cells or Mof heterozygosity in mice reduced mu gene expression. In this data set we compare proteins binding to the wild-type Emu versus a DNA bait control for which the E1 box of the core enhancer region was mutated (E1mt).The E1mt abrogates binding of proteins recognizing the E1 box (e.g. YY1). Max LFQ quantitative proteomics was employed in an approach incubating wild-type and control DNA with (unlabeled) nuclear extracts.
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Project description:The specificity of humoral immune responses depends on the functional rearrangement and expression of only one allele of immunoglobulin (Ig) genes. Here, we analyzed the comprehensive proteome of the murine Ig Emu enhancer, which governs the rearrangement and expression of the Ig mu heavy chain allele. By mass spectrometry of proteins bound at wild type versus mutant Emu enhancers, we identified Emu-binding proteins and associated multi-protein complexes. We found that the MSL/MOF complex, a regulator of gene dosage compensation in flies, binds Emu via transcription factor YY1 and facilitates Emu-driven chromatin looping and promoter interaction. Msl2 gene knockout in primary pre-B cells or Mof heterozygosity in mice reduced mu gene expression. In this data set we compare proteins binding to the wild-type Emu versus a DNA bait control for which the entire Emu sequence was switched to its reverse polarity sequence. The latter conserves the DNA GC content but virtually destroys all sequence-specific transcription factor binding sites. Of note, DNA repetitive sequences that can also be bound by DNA interacting proteins are kept functional by this control bait. SILAC quantitative proteomics was employed in a label swap approach incubating wild-type and control DNA with labeled and non-labled protein extracts, respectively.
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Project description:The specificity of humoral immune responses depends on the functional rearrangement and expression of only one allele of immunoglobulin (Ig) genes. Here, we analyzed the comprehensive proteome of the murine Ig Emu CORE enhancer, which governs the rearrangement and expression of the Ig mu heavy chain allele. The Ig Emu consists of a CORE enhancer (harboring a multitude of transcription factor binding sites) and two 5’ and 3’ flanking MAR (matrix attachment region) elements. By mass spectrometry of proteins bound at wild type versus mutant Emu enhancers, we identified Emu-binding proteins and associated multi-protein complexes. We found that the MSL/MOF complex, a regulator of gene dosage compensation in flies, binds Emu via transcription factor YY1 and facilitates Emu-driven chromatin looping and promoter interaction. Msl2 gene knockout in primary pre-B cells or Mof heterozygosity in mice reduced mu gene expression. In this data set we compare proteins binding to the wild-type Emu versus a DNA bait control for which the Emu CORE sequence was switched to its reverse polarity sequence (the flanking MARs sequence are wild-type). The latter conserves the DNA GC content but virtually destroys all sequence-specific transcription factor binding sites. Of note, DNA repetitive sequences that can also be bound by DNA interacting proteins are kept functional by this control bait. SILAC quantitative proteomics was employed in a label swap approach incubating wild-type and control DNA with labeled and non-labled protein extracts, respectively.
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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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