Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy

Cutrona, Giovanna; Matis, Serena; Colombo, Monica; Massucco, Carlotta; Baio, Gabriella; Valdora, Francesca; Emionite, Laura; Fabris, Sonia; Recchia, Anna Grazia; Gentile, Massimo; Neumaier, Carlo Emanuele; Reverberi, Daniele; Massara, Rosanna; Boccardo, Simona; Basso, Luca; Salvi, Sandra; Rosa, Francesca; Cilli, Michele; Zupo, Simona; Truini, Mauro; Tassone, Pierfrancesco; Calabrese, Massimo; Negrini, Massimo; Neri, Antonino; Morabito, Fortunato; Fais, Franco; Ferrarini, Manlio

doi:10.1038/leu.2016.394

Cited by 35 publications

(27 citation statements)

References 53 publications

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“…As a result, 7q deletion resulted in loss of heterozygosity of the BRAFV600E allele ( Figure 1D,F), as evidenced by the higher BRAFV600E variant allele frequency of 7q-deleted versus 7q-diploid cHCL (79% vs 22%, respectively; Wilcoxon matched-pairs signed rank test P 5 .0039). Recurrent 13q deletions in cHCL included the tumor suppressor RB1 and the miR-15a and miR-16-1 microRNA cluster at 13q14.3, which have been well studied in chronic lymphocytic leukemia 20 ( Figure 1E). …”

Section: Resultsmentioning

confidence: 99%

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

Durham¹,

Getta

Dietrich

et al. 2017

Blood

111

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Key Points• KMT2C mutations occur in 15% and 25% of patients with cHCL and vHCL, respectively, along with CCND3 and U2AF1 mutations each in 13% of vHCLs.• NF1, NF2, N/KRAS, and IRS1 alterations contribute to clinical resistance to vemurafenib treatment in patients with cHCL.Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation, whereas ∼30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n 5 53) and vHCL (n 5 8). The most common genetic alteration in cHCL apart from BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation. In addition to CDKN1B mutations in cHCL, recurrent inactivating mutations in KMT2C (MLL3) were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% of vHCLs harbored predicted activating mutations in CCND3.A change-of-function mutation in the splicing factor U2AF1 was also present in 13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in IRS1 and losses of NF1 and NF2, each of which contributed to resistance. These data provide further insight into the genetic bases of cHCL and vHCL and mechanisms of RAF inhibitor resistance encountered clinically. (Blood. 2017;130(14):1644-1648

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Section: Resultsmentioning

confidence: 99%

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

Durham¹,

Getta

Dietrich

et al. 2017

Blood

111

View full text Add to dashboard Cite

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“…MiR-16 is considered to be a tumor suppressor because it negatively regulates the expression of pro-oncogenic proteins involved in cell proliferation and cell death. Therefore, some studies aimed at expressing miR-16 as a therapeutic approach have been developed in a murine model of CLL 34,35 . However the use of micro RNAs as therapeutic tools remains rather unsuccessful as they have never progressed beyond a phase I trial 36 .…”

Section: Discussionmentioning

confidence: 99%

STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

Sueur

Boutet

Gotanègre

et al. 2020

Sci Rep

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We recently identified the CDC25A phosphatase as a key actor in proliferation and differentiation in acute myeloid leukemia expressing the FLT3-ITD mutation. In this paper we demonstrate that CDC25A level is controlled by a complex STAT5/miR-16 transcription and translation pathway working downstream of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR-16 restored CDC25A expression in response to FLT3-ITD inhibition. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation.

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“…MiR-16 is considered to be a tumor suppressor because it negatively regulates the expression of pro-oncogenic proteins involved in cell proliferation and cell death. Therefore, some studies aimed at expressing miR-16 as a therapeutic approach have been developed in a murine model of CLL (35, 36). However the use of micro RNAs as therapeutic tools remains rather unsuccessful as they have never progressed beyond a phase I trial (37).…”

Section: Discussionmentioning

confidence: 99%

STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

Sueur

Boutet

Gotanègre

et al. 2019

Preprint

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We recently identified the CDC25A phosphatase as a key actor in proliferation and differentiation in acute myeloid leukemia which expresses the FLT3-ITD mutation. In this paper we demonstrate that CDC25A level is controlled by a complex STAT5/miR-16 transcription and translation pathway working downstream of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR-16 restored CDC25A expression in response to FLT3-ITD inhibition. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation.

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Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy

Cited by 35 publications

References 53 publications

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

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