Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

Hoareau-Aveilla, Coralie; Valentin, Thibaud; Daugrois, Camille; Quelen, Cathy; Mitou, Géraldine; Quentin, Samuel; Jinsong, Jia; Spicuglia, Salvatore; Ferrier, Pierre; Ceccon, Monica; Giuriato, Sylvie; Gambacorti‐Passerini, Carlo; Brousset, Pierre; Lamant, Laurence

doi:10.1172/jci78488

Cited by 33 publications

(40 citation statements)

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“…Though the interplay between those microRNAs in autoimmunity progression is not fully comprehended, lessons can be learned by myasthenia gravis (MG), an autoantibody-mediated neuromuscular disorder (Punga et al 2015). MicroRNA-21 via inhibition of RASGRP1 gene expression downregulates DNA methyltransferase1 (DNMT1), and methylation-silencing of miR-150 gene by DNMT1 as recently reported (Hoareau-Aveilla et al 2015). Thus, we speculate that miR-21 may indirectly modulate miR-150 expression by downregulation of RASGRP1 that reduces expression of DNMT1 and hypomethylation may lead to the upregulation of miR-150 gene.…”

Section: Discussionmentioning

confidence: 98%

Enhanced expression of miR-21 and miR-150 is a feature of anti-mitochondrial antibody-negative primary biliary cholangitis

Wasik

Kempińska-Podhorodecka

Bogdanos

et al. 2020

Mol Med

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Background & Aims: Anti-mitochondrial-autoantibodies (AMA) remain a hallmark of Primary Biliary Cholangitis (PBC) however approximately 10% of patients test negative for these antibodies. They do not differ in terms of biochemistry or clinical presentation from AMA positive ones. Epigenetics play a key role in immune signalling. Two microRNAs (miRs), namely, miR-21 and miR-150 are known to be involved in liver inflammation and fibrosis. The expression of those two microRNAs and their downstream targets were analyze in the context of AMA-status and the stage of liver fibrosis. Methods: The relative levels of miR-21 and miR-150 and their target genes: cMyb, RAS-guanyl-releasing protein-1(RASGRP1), and DNA-methyltransferase-1(DNMT1) were determined by Real-Time PCR in serum, liver tissue and peripheral blood mononuclear cells (PBMCs) of patients with PBC. Results: Serum expressions of miR-21 and miR-150 were significantly enhanced in AMA-negative patients, and they inversely correlated with disease-specific AMA titers in PBS patients. In PBMCs, an increased expression of miR-21 correlated with decreased levels of RASGRP1 and DNMT1 mRNAs whereas, the level of miR-150 remained comparable to controls; and cMyb mRNA was downregulated. In cirrhotic livers, the level of miR-21 was unchanged while miR-150 expression was increased. Conclusion: This study convincingly report, that AMA-negative PBC is characterized by notable alternations of miR-21 and miR-150 and their downstream targets compared to AMA-positive patients underlining their possible importance in the induction of the disease and its progression to fibrosis.

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Section: Discussionmentioning

confidence: 98%

Enhanced expression of miR-21 and miR-150 is a feature of anti-mitochondrial antibody-negative primary biliary cholangitis

Wasik

Kempińska-Podhorodecka

Bogdanos

et al. 2020

Mol Med

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“…KLF2 is involved in lymphocyte biology (55), and miR-150 is involved in T-cell lineage commitment (56), B-cell differentiation (57), and natural killer cell development (58,59). In independent work, low miR-150 expression has been reported frequently for mantle cell lymphoma and in natural killer cell and T-cell lymphomas; furthermore, a loss of miR-150 contributes to increased proliferation, decreased apoptosis, and drug resistance in these malignancies (26,(60)(61)(62). Our work supports a role for both KLF2 and KLF4 regulation of miR-150 in hematopoietic malignancies but suggests that the loss of KLF4 is the major regulator in AML.…”

Section: Discussionmentioning

confidence: 99%

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Morris

Cummings

Korb

et al. 2016

Molecular and Cellular Biology

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bAcute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.A cute myeloid leukemia (AML) is characterized by increased self-renewal of leukemia stem or progenitor cells and a failure of differentiation to mature myeloid cells. Normal hematopoietic cell differentiation and proliferation are regulated by the expression and interaction of specific transcription factors (1, 2), which are altered in AML (3-5). Elucidation of the genomic landscape of AML has further highlighted that alterations in myeloid transcription factors play a significant role in leukemogenesis (4). Recent attention has focused on the role of aberrant expression of the Krüppel-like factor (KLF) family of transcription factors in cancer (5). This family includes 17 different isoforms that bind to GCrich regions of DNA via three zinc finger domains and regulate the transcriptional activity of target genes by using two glutaminerich transactivation domains (5). KLF4 regulates differentiation of epidermal and vascular smooth muscle cells (6, 7), as well as cellular reprogramming to induce pluripotent stem cells (8). In normal hematopoiesis, KLF2 and KLF4 regulate myeloid differentiation and KLF4 expression induces CDKN1A (p21), which contributes to cell cycle arrest (9-13). In T-cell acute lymphoblastic leukemia (T-ALL) (14) and B-cell lymphomas, KLF4 has been described as a tumor suppressor regulating proliferation, apoptosis, and differentiation (15). A recent study showed that the homeobox transcription factor CDX2 represses KLF4 in myeloid leukemia cells (16). The investigators also observed that C...

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“…In addition, recurrent activating mutations of JAK1 and/or STAT3 genes have been identified in 20% of cases (Crescenzo et al , ) and MIR155 overexpression has been detected (Merkel et al , , ). Undoubtedly as techniques develop, more defining (epi)genetic events will be described and other studies for example, have identified alterations to the epigenome in ALCL inclusive of CpG methylation and expression or down‐regulation of small non‐coding RNA sequences including miRNAs (Ambrogio et al , ; Merkel et al , , ; Zhang et al , ; Hoareau‐Aveilla et al , ).…”

Section: Genetics and Molecular Findingsmentioning

confidence: 99%

Anaplastic large cell lymphoma in paediatric and young adult patients

Lamant²,

et al. 2016

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Anaplastic large cell lymphoma (ALCL) is a heterogeneous disease of debateable origin that, in children, is largely anaplastic lymphoma kinase (ALK) positive with aberrant ALK activity induced following the formation of chromosomal translocations. Whilst the survival rates for this disease are relatively high, a significant proportion (20-40%) of patients suffer disease relapse, in some cases on multiple occasions and therefore suffer the toxic side-effects of combination chemotherapy. Traditionally, patients are treated with a combination of agents although recent data from relapse patients have suggested that low risk patients might benefit from single agent vinblastine and, going forward, the addition of ALK inhibitors to the therapeutic regimen may have beneficial consequences. There are also a plethora of other drugs that might be advantageous to patients with ALCL and many of these have been identified through laboratory research although the decision as to which drugs to implement in trials will not be trivial.

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Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

Abstract: International audienceno abstrac

Cited by 33 publications

References 79 publications

Enhanced expression of miR-21 and miR-150 is a feature of anti-mitochondrial antibody-negative primary biliary cholangitis

Enhanced expression of miR-21 and miR-150 is a feature of anti-mitochondrial antibody-negative primary biliary cholangitis

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Anaplastic large cell lymphoma in paediatric and young adult patients

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