MicroRNA-126–mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors

Okuyama, Kazuki; Ikawa, Tomokatsu; Gentner, Bernhard; Hozumi, Katsuto; Harnprasopwat, Ratanakanit; Lü, Jun; Yamashita, Riu; Ha, Daon; Toyoshima, Takae; Chanda, Bidisha; Kawamata, Toyotaka; Yokoyama, Kazuaki; Wang, Shusheng; Ando, Kiyoshi; Lodish, Harvey F.; Tojo, Arinobu; Kawamoto, Hiroshi; Kotani, Ai

doi:10.1073/pnas.1220710110

Cited by 31 publications

(32 citation statements)

References 46 publications

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“…Sustained miRNA-126 expression has direct effects on the B cell precursor compartment, including early lymphoid lineage priming (Okuyama et al, 2013), increased proliferation (Lechman et al, 2012), and-as shown in this work-reduced levels of apoptosis and delayed differentiation toward mature B cells. It is likely that collaborating mutations occur at the level of multipotent progenitors and/or B cell precursors in order to induce full-blown leukemia, and additional studies are warranted to define their nature and hierarchical occurrence in distinct progenitor cell subpopulations during the pre-leukemic phase in our model.…”

Section: Discussionsupporting

confidence: 65%

miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia

et al. 2016

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MicroRNA (miRNA)-126 is a known regulator of hematopoietic stem cell quiescence. We engineered murine hematopoiesis to express miRNA-126 across all differentiation stages. Thirty percent of mice developed monoclonal B cell leukemia, which was prevented or regressed when a tetracycline-repressible miRNA-126 cassette was switched off. Regression was accompanied by upregulation of cell-cycle regulators and B cell differentiation genes, and downregulation of oncogenic signaling pathways. Expression of dominant-negative p53 delayed blast clearance upon miRNA-126 switch-off, highlighting the relevance of p53 inhibition in miRNA-126 addiction. Forced miRNA-126 expression in mouse and human progenitors reduced p53 transcriptional activity through regulation of multiple p53-related targets. miRNA-126 is highly expressed in a subset of human B-ALL, and antagonizing miRNA-126 in ALL xenograft models triggered apoptosis and reduced disease burden.

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Section: Discussionsupporting

confidence: 65%

miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia

et al. 2016

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“…Simultaneously, the activation and proliferation of CD4 + SP cells also changed significantly. Similarly, miR-126 has also been reported to regulate the development of B cells from B cell progenitor cells [15]. Moreover, Agudo et al [16] found that miR-126 is critical for the survival and function of plasmacytoid dendritic cells (pDCs) and is involved in innate immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies show that miR-126 is also involved in the development and function of some types of immune cells [13,14]. For example, Okuyama et al [15] found that miR-126 is an important regulator in the development of B cells through controlling their expansion and proliferation, which alters the proportion of B cells from hematopoietic progenitor cells (HPCs) in the absence of early B-cell factor 1 (EBF1). Furthermore, Agudo et al [16] reported that miR-126 regulates the function of plasmacytoid dendritic cells (pDCs) and participates in the innate immune response induced by viruses and other microorganisms by targeting vascular endothelial growth factor receptor 2 (VEGFR2).…”

Section: Cd4mentioning

confidence: 99%

MicroRNA-126 Deficiency Affects the Development of Thymus CD4<sup>+</sup> Single-Positive Cells through Elevating IRS-1

et al. 2018

Int Arch Allergy Immunol

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Background: MicroRNA-126 (miR-126), a distinct miRNA family member, has been reported to be involved in the development and function of some types of immune cells. However, the potential role of miR-126 in the development of CD4⁺ T cells remains to be elucidated. Objectives: To investigate the potential role of miR-126 in the development of CD4⁺ T cells in the thymus and explore its significance. Methods: The relative expression level of miR-126 in thymus CD4⁺ single-positive (SP) cells was detected by Real-Time PCR assay. The possible change in thymus tissue was assessed by histopathology. The total cell number of thymocytes and the expression of activation-associated molecules including CD62L, CD69, and CD44, as well as proliferation-associated nuclear antigen Ki-67, in CD4⁺ SP cells were assessed by flow cytometric analysis. The expression of IRS-1 and related signaling pathways including Akt and Erk were determined by flow cytometric analysis. Results: Compared with that in wild-type (WT) mice, the total cell number of thymocytes in miR-126 knockdown (KD) mice increased significantly. Moreover, the proportion and absolute cell number of thymic CD4⁺ SP cells decreased significantly in miR-126 KD mice. Further analysis showed that the frequencies of activation-associated molecules including CD62L, CD69, and CD44, as well as proliferation-associated nuclear antigen Ki-67 in CD4⁺ SP cells also changed significantly, respectively. Mechanism aspect, the expression level of IRS-1, a putative target of miR-126, increased significantly in CD4⁺ SP cells in miR-126 KD mice. Moreover, the expression levels of the signaling molecules phosphorylated (p)-Akt and p-Erk also changed significantly. Conclusions: Our work is the first to reveal a previously unknown role of miR-126 in the development of CD4⁺ SP cells in the thymus, which might ultimately benefit studies on development of thymocytes.

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“…However, mice lacking miR-181 exhibited a modest impairment in B cell development only [22, 23], suggesting that the impact of miR-181 in B cell development remains to be elucidated. In addition, overexpression of miR-126 retrovirus in an immature B cell line derived from an acute lymphoblastic leukemia patient, and in mouse lin − HSPCs induced B cell differentiation through the regulation of insulin regulatory subunit-1 (IRS-1), an inhibitor of differentiation and proliferation [24]. However, how IRS-1 regulates B cell differentiation remains undetermined [24].…”

Section: Mirnas In B Cell Lineage Commitment: Mir-126 Mir23a Mir-132mentioning

confidence: 99%

miRNAs in B Cell Development and Lymphomagenesis

Coffre

Koralov

2017

Trends in Molecular Medicine

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B lymphocytes are essential for an efficient immune response against a variety of pathogens. A large fraction of hematologic malignancies is of B cell origin suggesting that development and activation of B cells need to be tightly regulated. In recent years, increasing evidence has emerged demonstrating that microRNAs (miRNAs) -- a class of non-coding RNAs that control gene expression -- are involved in the regulation of B cell development and function. Here, we provide an overview of the current knowledge on the role of miRNAs and their relevant targets in B cell development, B cell activation and B cell malignant transformation.

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MicroRNA-126–mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors

Cited by 31 publications

References 46 publications

miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia

miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia

MicroRNA-126 Deficiency Affects the Development of Thymus CD4<sup>+</sup> Single-Positive Cells through Elevating IRS-1

miRNAs in B Cell Development and Lymphomagenesis

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