Advertisement

ResearchIn-Press PreviewCell biologyHematology Open Access | 10.1172/jci.insight.192126

Insights and modulation of RNA polymerases-dependentR-loop and dsRNA inFanconi anemia hematopoietic stem cells

Michihiro Hashimoto,1 Xiaomin Feng,1 Jie Bai,1 Huimin Zeng,2 Tian Li,1 Jue Li,3 Terumasa Umemoto,4 Paul R. Andreassen,5 and Gang Huang1

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Hashimoto, M. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Feng, X. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Bai, J. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Zeng, H. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Li, T. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Li, J. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Umemoto, T. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Andreassen, P. in: PubMed | Google Scholar

1Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, United States of America

2Pediatric Department, Peking University People's Hospital, Beijing, China

3Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

4Laboratory of Stem Cell Engineering, Kumamoto University, Kumamoto, Japan

5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States of America

Find articles by Huang, G. in: PubMed | Google Scholar

Published February 26, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.192126.
Copyright © 2026, Hashimoto et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 26, 2026 - Version history
View PDF
Abstract

Fanconi anemia (FA) is the most common bone marrow failure (BMF) syndrome. Beyond a role in DNA repair, FA genes have a role in suppressing DNA-RNA hybrids, termed R-loops, which can be generated via RNA polymerase (RNAP)-mediated transcription. However, how these processes, including a role in fate determination of hematopoietic stem cells (HSCs), are related to BMF is largely unknown. Additionally, single FA gene knockouts in mice do not recapitulate most phenotypes observed in FA patients. Thus, we generated a mouse model for FA by introducing heterozygous Setd2, which restricts RNAP-dependent transcription. Here, we show that FA patient-derived cells and Setd2+/– Fanca–/– HSCs share increased R-loop as well as dsRNA levels, and a ribosomal biogenesis defect. Further, Setd2+/– Fanca–/– HSCs display cell cycle arrest, mitotic errors and BMF phenotypes. Importantly, utilizing our Setd2+/– Fanca–/– mice, we discovered that Juglone, a pan RNAP inhibitor, reduces R-loop and dsRNA and reverses ribosomal biogenesis defects and mitotic errors, thereby rescuing BMF. In conclusion, this study establishes a novel mouse model that underscores a key role for R-loop formation, ribosomal biogenesis defects and mitotic errors in HSCs in driving BMF in Fanconi anemia. We also introduce a potential therapeutic avenue based upon pan-inhibition of RNA polymerases utilizing Juglone.

Graphical Abstract
graphical abstract
Version history
  • Version 1 (February 26, 2026): In-Press Preview
Advertisement
Advertisement