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Epigenetic blueprint identifies poor outcome and hypomethylating agent-responsive T-ALL subgroup

ABSTRACT: Epigenetic blueprint identifies poor outcome and hypomethylating agent-responsive T-ALL subgroup

PROVIDER: PRJNA615905 | ENA |

REPOSITORIES: ENA

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Epigenetic blueprint identifies poor outcome and hypomethylating agent-responsive T-ALL subgroup

Project description:Adult T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy still associated with poor outcome calling for new therapeutic options. DNA methylation landscapes of adult T-ALL remain largely uncharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic sorted T-cell subpopulations and 143 primary adult T-ALLs as part of French GRAALL 2003-2005 trial. Our results indicated that T-ALL is epigenetically distinct from normal T-cell subpopulations and consisted of five major subtypes (C1-C5) which were either associating with co-occurring DNMT3A/IDH2 mutations (C1), TAL1 deregulation (C2), TLX3 (C3), TLX1/in cis-HOXA9 (C4) or in trans-HOXA9 (C5) overexpression. Importantly, our data identified an unexpected subset of hypermethylated T-ALL associated with poor outcome and primary therapeutic response. Using mouse xenografts, we showed that hypermethylated T-ALL samples displayed therapeutic response to the DNA hypomethylating agent, 5-Azacitidine, which significantly delayed tumor progression suggesting epigenetic-based therapies as a novel treatment option in hypermethylated T-ALL.

2021-03-01 | GSE147667 | GEO

Integrative Genomic Analysis of Medulloblastoma Identiﬁes a Molecular Subgroup That Drives Poor Clinical Outcome

Project description:Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183-96-182 expression, is associated with significantly lower rates of event-free and overall survivals. Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.

2022-05-03 | GSE202043 | GEO

Integrative Genomic Analysis of Medulloblastoma Identiﬁes a Molecular Subgroup That Drives Poor Clinical Outcome [DNA copy number]

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Integrative Genomic Analysis of Medulloblastoma Identiﬁes a Molecular Subgroup That Drives Poor Clinical Outcome

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An open-label, phase II basket study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors

Project description:Purpose: To evaluate whether administration of the oral DNA hypomethylating agent (HMA) CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.

2020-07-26 | GSE147537 | GEO

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