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Epigenetic silencing of miR-125b is required for normal B cell development

Li, Guideng and So, Alex Yick-Lun and Sookram, Reeshelle and Wong, Stephanie and Wang, Jessica K. and Ouyang, Yong and He, Peng and Su, Yapeng and Casellas, Rafael and Baltimore, David (2018) Epigenetic silencing of miR-125b is required for normal B cell development. Blood, 131 (17). pp. 1920-1930. ISSN 0006-4971. https://resolver.caltech.edu/CaltechAUTHORS:20180327-150057315

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Abstract

Deregulation of several microRNAs (miRs) can influence critical developmental checkpoints during hematopoiesis as well as cell functions, eventually leading to the development of autoimmune disease or cancer. We found that miR-125b is expressed in bone marrow multipotent progenitors and myeloid cells but shut down in the B-cell lineage, and the gene encoding miR-125b lacked transcriptional activation markers in B cells. To understand the biological importance of the physiological silencing of miR-125b expression in B cells, we drove its expression in the B-cell lineage and found that dysregulated miR-125b expression impaired egress of immature B cells from the bone marrow to peripheral blood. Such impairment appeared to be mediated primarily by inhibited expression of the sphingosine-1-phosphate receptor 1 (S1PR1). Enforced expression of S1PR1 or clustered regularly interspaced short palindromic repeats/Cas9–mediated genome editing of the miR-125b targeting site in the S1PR1 3′ untranslated region rescued the miR-125b–mediated defect in B-cell egress. In addition to impaired B-cell egress, miR-125b dysregulation initially reduced pre–B-cell output but later induced pre–B-cell lymphoma/leukemia in mice. Genetic deletion of IRF4 was found in miR-125b–induced B-cell cancer, but its role in oncogenic miR-125b–induced B-cell transformation is still unknown. Here, we further demonstrated an interaction of the effects of miR-125b and IRF4 in cancer induction by showing that miR125b-induced B-cell leukemia was greatly accelerated in IRF4 homozygous mutant mice. Thus, we conclude that physiological silencing of miR-125b is required for normal B-cell development and also acts as a mechanism of cancer suppression.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1182/blood-2018-01-824540DOIArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:© 2018 American Society of Hematology. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. Submitted December 29, 2017; Accepted March 5, 2018. The authors thank members of the D.B. laboratory for helpful discussions, Toshio Kitamura (The University of Tokyo) for providing Eμ/miR-125b-Tg mice, and Xun Wang for providing the retro-gRNA-CFP vector. This work was supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (RO1AI079243) (D.B.). Authorship: Contribution: G.L. designed research, performed experiments, analyzed results, and wrote the paper; A.Y.-L.S., R.S., Y.O., S.W., J.K.W., P.H., and Y.S. performed experiments; R.C. provided data and discussed the results; and D.B. designed research, discussed results, wrote the paper and provided financial support. The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
NIHRO1AI079243
Issue or Number:17
Record Number:CaltechAUTHORS:20180327-150057315
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180327-150057315
Official Citation:Epigenetic silencing of miR-125b is required for normal B-cell development Guideng Li, Alex Yick-Lun So, Reeshelle Sookram, Stephanie Wong, Jessica K. Wang, Yong Ouyang, Peng He, Yapeng Su, Rafael Casellas, David Baltimore Blood Apr 2018, 131 (17) 1920-1930; DOI: 10.1182/blood-2018-01-824540
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85468
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 Mar 2018 18:04
Last Modified:03 Oct 2019 19:31

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