Translocation t(6;7) in AML-M4 cell line GDM-1 results in MNX1 activation through enhancer-hijacking

Weichenhan, Dieter; Riedel, Anna; Meinen, Charlotte; Basic, Alisa; Tóth, Réka; Bähr, Marion; Lutsik, Pavlo; Hey, Joschka; Sollier, Etienne; Toprak, Umut; Kelekçi, Simge; Lin, Yu-Yu; Hakobyan, M. R.; Touzart, Aurore; Goyal, Ashish; Schlesner, Matthias; Westermann, Frank; Lipka, Daniel B.; Plass, Christoph

doi:10.1038/s41375-023-01865-5

Cited by 8 publications

(5 citation statements)

References 15 publications

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“…A few examples of enhancer-hijacking have been reported in the literature for myeloid leukemia in inv(3;3)/t(3;3) AML 11 and atypical 3q26/MECOM rearranged AML 12 . Enhancer-hijacking in the AML cell line, GDM-1, was recently reported as a result of a t(6;7)(q23;q36) and leads to activation of MNX1 through the interaction of the MNX1 promoter with an enhancer in the MYB locus 10 . Enhancer-hijacking events resulting in the activation of proto-oncogenes have been described also in other human malignancies including translocations resulting in the activation of oncogenes MYC , BCL2 or CCND1 in B-cell lymphoma 23–25 or rearrangements in medulloblastoma 26 .…”

Section: Discussionmentioning

confidence: 96%

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Altered enhancer-promoter interaction leads toMNX1expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Weichenhan,

Riedel,

Sollier

et al. 2023

Preprint

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Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor 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 downstream of 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.

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Section: Discussionmentioning

confidence: 96%

“…The first clue for the existence of possible aberrant promoter-enhancer interactions leading to MNX1 activation came from our investigations of the GDM-1 AML cell line which harbors a t(6;7)(q23;q36) translocation. In GDM-1, the MNX1 promoter interacts with an enhancer element from the MYB locus on chr6q23 10 .…”

Section: Introductionmentioning

confidence: 99%

Altered enhancer-promoter interaction leads toMNX1expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Weichenhan,

Riedel,

Sollier

et al. 2023

Preprint

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“…Cell lines continue to be a vital resource for functional studies. Several well-established cancer cell lines are highly rearranged, with underreported genomic complexity ( Nattestad et al, 2018 ; Aganezov et al, 2020 ; Weichenhan et al, 2023 ). Despite its frequent use for functional and mechanistic studies in leukemia research ( Oshima et al, 2020 ; Diedrich et al, 2021 ; Cousins et al, 2022 ; Leo et al, 2022 ; Wray et al, 2022 ), a comprehensive analysis of the complex REH genome has never been undertaken.…”

Section: Discussionmentioning

confidence: 99%

A multiomic characterization of the leukemia cell line REH using short- and long-read sequencing

Lysenkova Wiklander,

Arvidsson,

Bunikis

et al. 2024

Life Sci. Alliance

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The B-cell acute lymphoblastic leukemia (ALL) cell line REH, with the t(12;21)ETV6::RUNX1translocation, is known to have a complex karyotype defined by a series of large-scale chromosomal rearrangements. Taken from a 15-yr-old at relapse, the cell line offers a practical model for the study of pediatric B-ALL. In recent years, short- and long-read DNA and RNA sequencing have emerged as a complement to karyotyping techniques in the resolution of structural variants in an oncological context. Here, we explore the integration of long-read PacBio and Oxford Nanopore whole-genome sequencing, IsoSeq RNA sequencing, and short-read Illumina sequencing to create a detailed genomic and transcriptomic characterization of the REH cell line. Whole-genome sequencing clarified the molecular traits of disrupted ALL-associated genes includingCDKN2A,PAX5,BTG1,VPREB1, andTBL1XR1, as well as the glucocorticoid receptorNR3C1. Meanwhile, transcriptome sequencing identified seven fusion genes within the genomic breakpoints. Together, our extensive whole-genome investigation makes high-quality open-source data available to the leukemia genomics community.

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“…The alignments and “basemod_freq” tracks can display allele-specific DNA methylation. The leukemic cell line GDM-1 harbours a translocation between chromosomes six and seven, which activates MNX1 by enhancer hijacking 12 . By visualizing allele-specific methylation in this region using figeno, we observed allele-specific methylation, where the wild type allele is methylated at the MNX1 promoter while the rearranged allele is hypomethylated (Fig.1D).…”

Section: Figeno: a Flexible Versatile And User-friendly Solution For ...mentioning

confidence: 99%

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

Sollier,

Heilmann,

Gerhäuser

et al. 2024

Preprint

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The 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. Figeno 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.

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Translocation t(6;7) in AML-M4 cell line GDM-1 results in MNX1 activation through enhancer-hijacking

Cited by 8 publications

References 15 publications

Altered enhancer-promoter interaction leads toMNX1expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Altered enhancer-promoter interaction leads toMNX1expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

A multiomic characterization of the leukemia cell line REH using short- and long-read sequencing

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

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