Altered enhancer-promoter interaction leads to <i>MNX1</i> 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 break point partners (motor neuron and pancreas homeobox 1 [MNX1] and ETS variant transcription factor 6 [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 break points 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 is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) induced pluripotent stem cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer hijacking may be a more widespread consequence of translocations in which no oncofusion product was identified, including t(1;3) or t(4;12) AML.
Authors
- Anna Riedel (ORCID: https://orcid.org/0000-0002-0626-3894)
- Pavlo Lutsik (ORCID: https://orcid.org/0000-0001-9383-8555)
- Hartmann Harz (ORCID: https://orcid.org/0000-0003-1218-2107)
- Susanna Jacobsson
- Daniel B. Lipka (ORCID: https://orcid.org/0000-0001-5081-7869)
- Christoph Plass (ORCID: https://orcid.org/0000-0003-2554-3952)
- Yvonne Lisa Behrens (ORCID: https://orcid.org/0000-0002-2390-0541)
- Aurore Touzart (ORCID: https://orcid.org/0000-0002-8888-2292)
- Clemens Steinek (ORCID: https://orcid.org/0000-0003-3590-2103)
- Brigitte Schlegelberger (ORCID: https://orcid.org/0000-0001-5256-1270)
- Heinrich Leonhardt (ORCID: https://orcid.org/0000-0002-5086-6449)
- Marion Bähr (ORCID: https://orcid.org/0009-0000-2942-0701)
- Lars Bullinger (ORCID: https://orcid.org/0000-0002-5890-5510)
- Anna Dolnik (ORCID: https://orcid.org/0000-0003-4166-2900)
- Kersten Breuer (ORCID: https://orcid.org/0000-0003-3716-7739)
- Dieter Weichenhan (ORCID: https://orcid.org/0000-0002-7915-412X)
- Joschka Hey (ORCID: https://orcid.org/0000-0003-2842-764X)
- Lars Palmqvist (ORCID: https://orcid.org/0000-0001-9274-360X)
- Gudrun Göhring (ORCID: https://orcid.org/0000-0002-0863-8645)
- Dirk Reinhardt (ORCID: https://orcid.org/0000-0002-7027-4483)
- Etienne Sollier (ORCID: https://orcid.org/0000-0002-3612-8562)
- Ahmed Waraky (ORCID: https://orcid.org/0000-0003-4635-021X)
- Justyna A. Wierzbińska (ORCID: https://orcid.org/0000-0001-5536-3501)
- Umut H. Toprak (ORCID: https://orcid.org/0009-0009-6923-6816)
- Tina Nilsson
- Anders Östlund
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Sahlgrenska University Hospital (SE)
- University Hospital Heidelberg (DE)
- Medizinische Hochschule Hannover (DE)
- Humboldt-Universität zu Berlin (DE)
- National Center for Tumor Diseases (DE)
- Essen University Hospital (DE)
- Max Planck Institute of Neurobiology (DE)
- Oxford Nanopore Technologies (United Kingdom) (GB)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University of Duisburg-Essen (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Ludwig-Maximilians-Universität München (DE)
- Epigenomics (Germany) (DE)
- University of Gothenburg (SE)
Publication Details
- Journal
- Blood Advances
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1182/bloodadvances.2023012161
- Citations
- 17
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 7.72
Funders
- Västra Götalandsregionen
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft
- Cancerfonden
- José Carreras Leukämie-Stiftung
- Barncancerfonden