Biology subjects

Sollier, E.

Publications and source records attributed to Sollier, E..

6 recordsLinked to original sources

bioRxiv2024

Acute Myeloid Leukemia with deletion 5q is an epigenetically distinct subgroup defined by heterozygous loss of KDM3B

Acute myeloid leukemia (AML) is a hematological malignancy characterized by a block in differentiation and accelerated proliferation of myeloid progenitor cells. Genes encoding for epigenetic regulators are among the most frequent targets for mutations and structural variations in AML, giving rise to profound epigenetic heterogeneity between and within tumors. Deletions of chromosome 5q [del(5q)] are among the most common copy number alterations in AML and are associated with extremely poor clinical outcome and therapy resistance, however the mechanisms linking del(5q) to leukemic progression are not understood. Analyzing DNA methylation profiles from 477 elderly AML patients using DNA methylome deconvolution, we discovered that del(5q) AML is an epigenetically distinct subgroup characterized by a signature of DNA hypermethylation, which we propose may be linked to dysregulation of H3K9me1/2 and overexpression of the leukemic stem cell marker, DNMT3B. Interrogation of the minimally deleted 5q region highlighted the H3K9me1/2 demethylase KDM3B as a likely target for haploinsufficiency in this subgroup. Our data suggest that del(5q) AML should be reconsidered as an epigenetically dysregulated subgroup, driven by heterozygous loss of KDM3B, and that the resulting imbalance of H3K9me1/2 may contribute to the progression of these aggressive leukemias.

cancer biology↗

bioRxiv2024

Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q

Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML. Statement of significanceThis study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism.

cancer biology↗

bioRxiv2024

SRSF2 transcriptional function maintains genome integrity during cell division

Recurrent mutations in serine / arginine-rich splicing factor 2 (SRSF2), particularly the proline-to-histidine substitution at position 95 (P95H), have been proposed to drive neoplastic diseases. SRSF2 plays pivotal roles in pre-mRNA processing and gene transcription. However, the precise impact of these diverse functions of SRSF2 on cancer cell behaviour remains unclear. Here, we show that deletion or homozygous P95H mutation of SRSF2 both cause extensive DNA damage leading to cell cycle arrest in vitro and in vivo, regardless of cell genotype. We mechanistically demonstrate that SRSF2 is required for efficient bi-directional transcription of DNA replication and repair genes, independent of its function in splicing. In contrast, SRSF2 haploinsufficiency induces DNA damage without halting the cell cycle in cancer cells. Inducing the heterozygous Srsf2 P95H mutation leads to clonal expansion of epidermal cells in mouse skin, but tumor formation is inhibited following exposure to carcinogens. To survive carcinogen treatment, cells containing the Srsf2 P95H mutation undergo substantial transcription rewiring that restores bi-directional gene expression. Thus, our study reveals crucial roles of SRSF2 beyond splicing and underscores its importance in regulating transcription to orchestrate the cell cycle along with the DNA damage response.

cell biology↗

bioRxiv2024

Figeno: multi-region genomic figures with long-read support

SummaryThe vast amount of publicly available genomic data requires analysis and visualization tools. Here, we present figeno, an application for generating publication-quality FIgures for GENOmics. Figeno particularly focuses on multi-region views across genomic breakpoints and on long reads with base modifications. Additionally, we support epigenomic data including ATAC-seq, ChIP-seq or HiC, as well as whole genome sequencing data with copy numbers and structural variants. Availability and ImplementationFigeno is available as a python package with both a command line and graphical user interface. It can be installed via PyPI and the source code is available at https://github.com/CompEpigen/figeno. Supplementary informationSupplementary data is provided.

bioinformatics↗

bioRxiv2023

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML (n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking is a more common and overlooked mechanism for structural rearrangement-mediated gene activation in AML. Key pointsO_LIExpression analysis of over 1500 pediatric AML samples demonstrates MNX1 expression as a universal feature of t(7;12)(q36;p13) AML as well as in rare cases without t(7;12)(q36;p13) C_LIO_LIMNX1 is activated by an enhancer-hijacking event in t(7;12)(q36;p13) AML and not, as previously postulated, by the creation of a MNX1::ETV6 oncofusion gene. C_LI

cancer biology↗

bioRxiv2022

Joint copy number and mutation phylogeny reconstruction fromsingle-cell amplicon sequencing data

Reconstructing the history of somatic DNA alterations can help understand the evolution of a tumor and predict its resistance to treatment. Single-cell DNA sequencing (scDNAseq) can be used to investigate clonal heterogeneity and to inform phylogeny reconstruction. However, most existing phylogenetic methods for scDNAseq data are designed either for single nucleotide variants (SNVs) or for large copy number alterations (CNAs), or are not applicable to targeted sequencing. Here, we develop COMPASS, a computational method for inferring the joint phylogeny of SNVs and CNAs from targeted scDNAseq data. We evaluate COMPASS on simulated data and apply it to several datasets including a cohort of 123 patients with acute myeloid leukemia. COMPASS detected clonal CNAs that could be orthogonally validated with bulk data, in addition to subclonal ones that require single-cell resolution, some of which point toward convergent evolution.

bioinformatics↗