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Ablation of miR-146b in mice causes hematopoietic malignancy

Mitsumura, Takahiro, Ito, Yoshiaki, Chiba, Tomoki, Matsushima, Takahide, Kurimoto, Ryota, Tanaka, Yoko, Kato, Tomomi, Uchida, Keisuke, Ito, Takashi, Yamamoto, Kouhei, Eishi, Yoshinobu, Kitagawa, Masanobu, Miyazaki, Yasunari, Inase, Naohiko, Asahara, Hiroshi·2018·Blood Advances
DOI 10.1182/bloodadvances.2018017954
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Abstract

Excessive and constitutive activation of nuclear factor-κB (NF-κB) leads to abnormal cell proliferation and differentiation, leading to the development of malignant tumors, including lymphoma. MicroRNA 146a (miR-146a) and miR-146b, both of which carry an identical seed sequence, have been shown to contribute to inflammatory diseases and tumors by suppressing the expression of key molecules required for NF-κB activation. However, the functional and physiological differences between miR-146a and miR-146b in disease onset have not been fully elucidated. In this study, we generated miR-146b–knockout (KO) and miR-146a–KO mice by genome editing and found that both strains developed hematopoietic malignancies such as B-cell lymphoma and acute myeloid leukemia during aging. However, the B-cell lymphomas observed in miR-146a– and miR-146b–KO mice were histologically different in their morphology, and the malignancy rate is lower in miR-146b mice than miR-146a mice. Upon mitogenic stimulation, the expression of miR-146a and miR-146b was increased, but miR-146b expression was lower than that of miR-146a. Using a previously developed screening system for microRNA targets, we observed that miR-146a and miR-146b could target the same mRNAs, including TRAF6, and inhibit subsequent NF-κB activity. Consistent with these findings, both miR-146a– and miR-146b–KO B cells showed a high proliferative capacity. Taken together, sustained NF-κB activation in miR-146b KO mice could lead to the development of hematopoietic malignancy with aging.

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Figure 1 Production of miR-146a and miR-146b KO mice with TALEN. (A) Genetic deletion in miR-146a -and miR-146b -deficient mice generated by TALEN. The genomic sequence is shown at the top, with the target sequences of a pair of TALEN colored in red. Blue lines and boxes indicate pre-miRNA and mature miRNA sequences, respectively. Deleted nucleotides are indicated with dashes. The sizes of the deletions and insertions are shown to the right of the mutated alleles with D . WT indicates alleles without a mutation. (B) RT-PCR analysis of miR-146a and miR-146b in liver tissue derived from mutant mice. The genotype of each animal is indicated at the bottom. The expression level of miR-146a and miR-146b in the WT animal was adjusted to 1.
Figure 1 Production of miR-146a and miR-146b KO mice with TALEN. (A) Genetic deletion in miR-146a -and miR-146b -deficient mice generated by TALEN. The genomic sequence is shown at the top, with the target sequences of a pair of TALEN colored in red. Blue lines and boxes indicate pre-miRNA and mature miRNA sequences, respectively. Deleted nucleotides are indicated with dashes. The sizes of the deletions and insertions are shown to the right of the mutated alleles with D . WT indicates alleles without a mutation. (B) RT-PCR analysis of miR-146a and miR-146b in liver tissue derived from mutant mice. The genotype of each animal is indicated at the bottom. The expression level of miR-146a and miR-146b in the WT animal was adjusted to 1.CC-BY-NC-ND · From the PDF
Figure 2 Histological analysis of spleens and lymph nodes in WT mice and representative malignancies in miR-146a or miR-146b KO mice. (A) Increased rate of tumorigenesis in mice with miR-146a or miR-146b ablation. n 5 11 (WT), 8 (miR-146a KO1), 3 (miR-146a KO2), and 21 (miR-146b KO). (B) Photograph of spleens isolated from WT and miR-146b KO mice at 16 months. (C) miR-146a and miR-146b KO mice developed B-cell lymphomas in the spleen and lymph nodes. Scale bars represent 500 m m (low magnification), 20 m m (high magnification), and 2.5 m m (insets). (D) miR-146b KO mice developed acute leukemia. Scale bars represent 500 m m (low magnification) and 20 m m (high magnification), and 2.5 m m (inset). HE, hematoxylin and eosin; FL, follicular lymphoma.
Figure 2 Histological analysis of spleens and lymph nodes in WT mice and representative malignancies in miR-146a or miR-146b KO mice. (A) Increased rate of tumorigenesis in mice with miR-146a or miR-146b ablation. n 5 11 (WT), 8 (miR-146a KO1), 3 (miR-146a KO2), and 21 (miR-146b KO). (B) Photograph of spleens isolated from WT and miR-146b KO mice at 16 months. (C) miR-146a and miR-146b KO mice developed B-cell lymphomas in the spleen and lymph nodes. Scale bars represent 500 m m (low magnification), 20 m m (high magnification), and 2.5 m m (insets). (D) miR-146b KO mice developed acute leukemia. Scale bars represent 500 m m (low magnification) and 20 m m (high magnification), and 2.5 m m (inset). HE, hematoxylin and eosin; FL, follicular lymphoma.CC-BY-NC-ND · From the PDF
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CC-BY-NC-ND · From the PDF
Figure 4 Suppression of NFk B activity by miR-146a and miR-146b. (A) Luciferase reporter assay for miR-146a -or miR-146b -dependent regulation of NFk B. Luciferase activity was measured in HEK293T cells transfected with a control empty vector, miR-146a, or miR-146b expression vector (with or without 50 ng/mL PMA). Data are presented as the mean 6 SEM. Two independent experiments were performed, and similar results were obtained. 1 , 5 ng; 11 , 75 ng. (B) Luciferase reporter assays in 293FT cells transfected with pcDNA-miR-146a (miR-146a), pcDNA-miR-146b (miR-146b), or an empty vector (Ctrl). MCS, pLuc2-KAP-MCS (multicloning site as an empty reporter). Data are presented as the mean 6 SEM; n 5 3. (C) Western blot analysis of TRAF6 protein expression in nonstimulated WT and miR-146a or miR-146b KO splenic B cells and those stimulated with LPS or anti-CD40 antibody. Two mice per genotype were analyzed; representative results are shown. * P , .05, ** P , .01.
Figure 4 Suppression of NFk B activity by miR-146a and miR-146b. (A) Luciferase reporter assay for miR-146a -or miR-146b -dependent regulation of NFk B. Luciferase activity was measured in HEK293T cells transfected with a control empty vector, miR-146a, or miR-146b expression vector (with or without 50 ng/mL PMA). Data are presented as the mean 6 SEM. Two independent experiments were performed, and similar results were obtained. 1 , 5 ng; 11 , 75 ng. (B) Luciferase reporter assays in 293FT cells transfected with pcDNA-miR-146a (miR-146a), pcDNA-miR-146b (miR-146b), or an empty vector (Ctrl). MCS, pLuc2-KAP-MCS (multicloning site as an empty reporter). Data are presented as the mean 6 SEM; n 5 3. (C) Western blot analysis of TRAF6 protein expression in nonstimulated WT and miR-146a or miR-146b KO splenic B cells and those stimulated with LPS or anti-CD40 antibody. Two mice per genotype were analyzed; representative results are shown. * P , .05, ** P , .01.CC-BY-NC-ND · From the PDF
Figure 5 Proliferation of WT, miR-146a KO, and miR-146b KO B cells in response to LPS, anti-CD40, and anti-IgM antibody. Splenic B cells (CD19 1 ) were incubated for 48 hours in the presence of media only (none) or the indicated mitogens (0.1, 1, or 10 m g/mL LPS; 0.1, 1, or 5 m g/mL anti-CD40; and 10 m g/mL anti-IgM). Proliferation was measured by [ 3 H]-thymidine incorporation. Data are presented as mean 6 SEM. n 5 6. * P , .05, ** P , .01. cpm, counts per minute.
Figure 5 Proliferation of WT, miR-146a KO, and miR-146b KO B cells in response to LPS, anti-CD40, and anti-IgM antibody. Splenic B cells (CD19 1 ) were incubated for 48 hours in the presence of media only (none) or the indicated mitogens (0.1, 1, or 10 m g/mL LPS; 0.1, 1, or 5 m g/mL anti-CD40; and 10 m g/mL anti-IgM). Proliferation was measured by [ 3 H]-thymidine incorporation. Data are presented as mean 6 SEM. n 5 6. * P , .05, ** P , .01. cpm, counts per minute.CC-BY-NC-ND · From the PDF

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Citations

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Metadata

Authors
Mitsumura, T., Ito, Y., Chiba, T., Matsushima, T., Kurimoto, R., Tanaka, Y., Kato, T., Uchida, K., Ito, T., Yamamoto, K., Eishi, Y., Kitagawa, M., Miyazaki, Y., Inase, N., & Asahara, H.
Affiliations
  • Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences,
  • Division of Surgical Pathology, Tokyo Medical and Dental University Hospital, Tokyo, Japan;
  • Department of Human Pathology and
  • Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; and
  • Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, and
ORCID
Venue
Blood Advances
Publisher
American Society of Hematology
Published
2018-12-07
Volume
2
Issue
23
Pages
3483-3491
ISSN
  • 2473-9529
  • 2473-9537
DOI
10.1182/bloodadvances.2018017954
Cited by
22
References
4
Language
en

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CoChat. (2026). Citation check: Ablation of miR-146b in mice causes hematopoietic malignancy. https://app.cochat.ai/papers/10.1182/bloodadvances.2018017954
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Mitsumura, T., Ito, Y., Chiba, T., Matsushima, T., Kurimoto, R., Tanaka, Y., Kato, T., Uchida, K., Ito, T., Yamamoto, K., Eishi, Y., Kitagawa, M., Miyazaki, Y., Inase, N., & Asahara, H. (2018). Ablation of miR-146b in mice causes hematopoietic malignancy. Blood Advances. https://doi.org/10.1182/bloodadvances.2018017954