A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies

Ortega, Manoela Marques; Bhatnagar, Harshita; Lin, Anping; Wang, Long; Aster, Jon C.; Sill, Heinz; Aguiar, Ricardo C.T.

doi:10.1038/leu.2014.302

Cited by 60 publications

(57 citation statements)

References 38 publications

(61 reference statements)

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“…RNA isolation and cDNA generation were performed as we described previously (26). Real-time RT-PCR was used to quantify the expression of the cyclin-dependent kinase inhibitors (CDKi) p15 (Cdkn2b), p16 (Cdkn2a), p21 (Cdkn1a), and p57 (Cdkn1c) as well as the expression of the p53 transcriptional targets Cdc25c, Gadd45a, and Pcna.…”

Section: Methodsmentioning

confidence: 99%

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MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

Bouamar

Jiang

Wang

et al. 2015

Molecular and Cellular Biology

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In biological processes, the balance between positive and negative inputs is critical for an effective physiological response and to prevent disease. A case in point is the germinal center (GC) reaction, wherein high mutational and proliferation rates are accompanied by an obligatory suppression of the DNA repair machinery. Understandably, when the GC reaction goes awry, loss of immune cells or lymphoid cancer ensues. Here, we detail the functional interactions that make microRNA 155 (miR-155) a key part of this process. Upon antigen exposure, miR-155 ؊/؊ mature B cells displayed significantly higher double-strand DNA break (DSB) accumulation and p53 activation than their miR-155 ؉/؉ counterparts. Using B cell-specific knockdown strategies, we confirmed the role of the miR-155 target Aicda (activation-induced cytidine deaminase) in this process and, in combination with a gain-of-function model, unveiled a previously unappreciated role for Socs1 in directly modulating p53 activity and the DNA damage response in B lymphocytes. Thus, miR-155 controls the outcome of the GC reaction by modulating its initiation (Aicda) and termination (Socs1/p53 response), suggesting a mechanism to explain the quantitative defect in germinal center B cells found in mice lacking or overexpressing this miRNA. Somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin genes are critical steps for the development of fully functional mature B cells. Several components of the cellular machinery that promotes SHM and CSR have been identified. Activation-induced cytidine deaminase (Aicda), an enzyme that deaminates cytosine to produce uracil in DNA, is thought to initiate and be essential for both SHM and CSR (1). Activation of uracil DNA glycosylase (UNG), ATM, histone H2AX, p53 binding protein 1 (53BP1), and the nonhomologous end joining protein Ku70/80, among others, also plays important roles in these processes (1, 2).The physiological SHM and CSR involve DNA mutagenesis and double-strand DNA breaks (DSB). Thus, the cellular response to these injuries must be fine-tuned so as to neither excessively engage the repair checkpoints nor compromise the integrity of the rest of the genome (3). Transient transcription repression of multiple DNA repair genes by BCL6 and high-fidelity repair of nonimmunoglobulin genes account, at least in part, for a successful germinal center (GC) response (3-7). Furthermore, timely engagement of the p53 pathway protects against AID-dependent aberrant DNA damage and chromosomal translocations (8). However, less is known about the termination of these activities, which is a critical step to prevent loss of normal B lymphocytes.MicroRNAs (miRNAs) are non-protein-coding small RNAs that regulate a vast array of physiological functions. miRNAs subtly downmodulate the expression of multiple proteins, thus functioning primarily as rheostats that match the cell needs seamlessly but effectively (9, 10). This unique property suggests that miRNAs may contribute to the control of SHM and CSR react...

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Section: Methodsmentioning

confidence: 99%

“…Relative expression of miR-155 was defined by stem-loop quantitative TaqMan real-time reverse transcription-PCR (RT-PCR) assay (MicroRNA assays; Applied Biosystems Inc.). Small nucleolar (Sno) RNA 202 was used for normalizing the expression, as described previously (26).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

Bouamar

Jiang

Wang

et al. 2015

Molecular and Cellular Biology

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“…71 MYC may also activate NOTCH1 via a positive feedback mechanism, as MYC suppresses the expression of miRNA-30, which targets the 3' untranslated region of NOTCH1 ( Figure 2C). 72 Accordingly, treatment of T-ALL xenografted mice with the bromodomain protein inhibitor JQ1 results in decreased MYC levels and also reverses MYC-induced resistance to GSI. 73,74 Furthermore, in human T-ALL cell lines, GSI-sensitive cells can be converted to being GSI-resistant by the ectopic expression of MYC.…”

Section: Rd Mendes Et Almentioning

confidence: 99%

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

et al. 2016

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T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of developing T cells in the thymus. T-ALL is characterized by chromosomal rearrangements. These rearrangements can lead to the aberrant activation of oncogenic transcription factors by placing their genes under the control of promoters and/or enhancers of Tcell receptor genes, the BCL11B gene, or other genes; occasionally, these rearrangements can give rise to oncogenic fusion proteins. The activated oncogenic transcription factors include TAL1 and LMO2 (and related family members), TLX1, TLX3, NKX2-1, HOXA, and MEF2C; in addition, certain oncogenic fusion proteins can directly activate the HOXA or MEF2C genes.1,2 Oncogenic proteins facilitate the developmental arrest of pre-leukemic immature T cells. We previously proposed that these chromosomal rearrangements should be classified as type A aberrations, as they are generally considered to be the driving oncogenic event associated with unique expression profiles.2 Based upon their gene expression signatures, T-ALL can be classified into the following four major subtypes: ETP-ALL, TLX, proliferative, and TALLMO. [3][4][5] Maturation arrest induces a pre-leukemic condition in which additional mutations can give rise to T-ALL.1,2 These secondary mutations are not necessarily clonal events and are often selected during disease progression or post-treatment T he tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycoly sis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.

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“…É sabido que miRNAs podem regular a via Notch em diferentes situações ORTEGA et al, 2015;, sendo demonstrada a ação repressora do miR-363-3p sobre esta via por meio do bloqueio da produção de NOTCH1 , porém o papel dos miRNAs diretamente na regulação de Notch em células pluripotentes ainda não foi explorado e as implicações desta regulação são desconhecidas. Com os dados aqui gerados e em conjunto com o conhecimento existente na literatura, pode-se hipotetizar um mecanismo de regulação da pluripotência por ação do miR-363-3p, onde este reprime a ativação da via Notch por knockdown de componentes desta via, como PSEN1 e NOTCH, impedindo assim o efeito indutor de diferenciação desempenhado por HES1 e promovendo autorrenovação e manutenção do status pluripotente.…”

Section: Inibição Da Viaunclassified

“…It is known that miRNAs can regulate the Notch pathway in different situations , ORTEGA et al, 2015, demonstrating the repressive action of miR-363-3p on this pathway by However, the role of miRNAs directly in the regulation of Notch in pluripotent cells has not yet been explored and the implications of this regulation are unknown. With the data generated here and together with the existing literature knowledge, it is possible to hypothesize a mechanism of regulation of pluripotency by action of miR-363-3p, where it represses the activation of the Notch pathway by knockdown of components of this pathway, as PSEN1 and NOTCH, thus preventing the inducing effect of differentiation performed by HES1 and promoting self renewal and maintenance of pluripotent status.…”

Section: Inhibition Of the Notch Pathway By Mirnas Promotes Pluripotementioning

confidence: 99%

Identificação de vias moduladas por microRNAs na diferenciação celular e manutenção da pluripotência em células humanas

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A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies

Cited by 60 publications

References 38 publications

MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

Identificação de vias moduladas por microRNAs na diferenciação celular e manutenção da pluripotência em células humanas

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