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

Blood. 2018 Apr 26;131(17):1920-1930. doi: 10.1182/blood-2018-01-824540. Epub 2018 Mar 19.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / pathology
  • Epigenetic Repression*
  • Gene Expression Regulation, Leukemic*
  • Gene Silencing*
  • HEK293 Cells
  • Humans
  • Mice
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics


  • MicroRNAs
  • Mirn125 microRNA, mouse
  • Neoplasm Proteins
  • RNA, Neoplasm