Trisomy 8 alters chromatin conformations and activates Y chromosome genes in stem cells to drive a pre-leukemic state
The mechanistic role of trisomy 8 in the development of myelodysplastic syndrome (MDS) remains poorly defined. Here, we generated a trisomy 8 mouse model by transferring a human chromosome 8 into murine embryonic stem cells and prospectively examined the effects on hematopoietic stem cells (HSC) by trisomy 8. The expression of inflammatory genes was enhanced, and hematopoietic programs mediated by transcription factors and polycomb repressive complex 2 (PRC2) were dysregulated in trisomy 8 HSC, which impaired their self-renewal and balanced differentiation. Trisomy 8 HSC altered the chromatin accessibility and conformations and activated Y chromosome genes, such as Uty/Kdm6c epigenetic modifier, which is known to demethylate histone H3K27me3 modification. The Uty gene facilitated the activation of PRC2-target and Runx1-target genes in leukemogenesis and drove the proliferation of human trisomy 8 leukemic cells. Since the RUNX1 gene is frequently mutated in patients with trisomy 8 MDS, its deletion attenuated the enhanced expression of inflammatory genes and mitigated the impaired self-renewal of trisomy 8 HSC in mice. Our findings reveal that trisomy 8 altered the transcriptional programs and chromatin conformations in HSC and drove a pre-malignant state through activating the expression of Uty, suggesting a route for the development of trisomy 8 MDS.
Authors
- Yasuhiro Kazuki (ORCID: https://orcid.org/0000-0003-4818-4710)
- Sho Kubota (ORCID: https://orcid.org/0000-0001-6119-1259)
- Kensaku Kohrogi (ORCID: https://orcid.org/0000-0001-6691-5439)
- Supannika Sorin (ORCID: https://orcid.org/0000-0002-5075-0139)
- Narumi Uno (ORCID: https://orcid.org/0000-0002-4218-1167)
- Minetaro Ogawa (ORCID: https://orcid.org/0000-0002-4104-8911)
- Goro Sashida (ORCID: https://orcid.org/0000-0003-2318-5987)
- Kimi Araki (ORCID: https://orcid.org/0000-0002-1396-1527)
- Daisuke Kurotaki (ORCID: https://orcid.org/0000-0002-4728-0113)
- Minoru Terashima (ORCID: https://orcid.org/0000-0002-5688-5181)
- Ai Hamashima (ORCID: https://orcid.org/0000-0002-1683-4443)
- Mihoko Iimori (ORCID: https://orcid.org/0000-0001-6777-4770)
- Kei Hiramatsu
- Eerdunduleng
- Jie Bai
- Mitsuo Oshimura
- Gang Huang
- Kenta Kikuchi
Institutions
- Tokyo University of Pharmacy and Life Sciences (JP)
- Okayama University (JP)
- The University of Texas at San Antonio Health Science Center (US)
- National Institutes of Natural Sciences (JP)
- Tottori University (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- Oncogene
- Published
- 2026-04-03
- DOI
- https://doi.org/10.1038/s41388-026-03763-3
- Primary Topic
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Japanese Society of Hematology
- Ministry of Education, Culture, Sports, Science and Technology
- Astellas Pharma
- Astellas Foundation for Research on Metabolic Disorders
- Soochow University
- Princess Takamatsu Cancer Research Fund
- Chugai Pharmaceutical
- Japan Society for the Promotion of Science
- Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences