MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment

Pierpaolo Leoncini, Alice Bertaina, Dimitrios Papaioannou, Christian Flotho, Riccardo Masetti, S. Bresolin, Giuseppe Menna, N. Santoro, Marco Zecca, Giuseppe Basso, Giovanni Nigita, Dario Veneziano, Sara Pagotto, Katia D'Ovidio, Rossella Rota, Adrienne Dorrance, Carlo M. Croce, C. M. Niemeyer, Franco Locatelli, Ramiro Garzon

Research output: Contribution to journalArticle

Abstract

Juvenile myelomonocytic leukemia (JMML) is an aggressive leukemia of early childhood characterized by aberrant proliferation of myelomonocytic cells and hypersensitivity to GM-CSF stimulation. Mutually exclusive mutations in the RAS/ERK pathway genes such as PTPN11, NRAS, KRAS, CBL, or NF1 are found in ~90% of the cases. These mutations give rise to disease at least in part by activating STAT5 through phosphorylation and by promoting cell growth. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression, which are often deregulated in leukemia. However, little is known about their role in JMML. Here, we report distinctive miR expression signatures associated with the molecular subgroups of JMML. Among the downregulated miRs in JMML, miR-150-5p was found to target STAT5b, a gene which is often over-activated in JMML, and contributes to the characteristic aberrant signaling of this disorder. Moreover, loss of miR-150-5p and upregulation of STAT5b expression were also identified in a murine model of JMML. Ectopic overexpression of miR-150-5p in mononuclear cells from three JMML patients significantly decreased cell proliferation. Altogether, our data indicate that miR expression is deregulated in JMML and may play a role in the pathogenesis of this disorder by modulating key effectors of cytokine receptor pathways.

Original languageEnglish
Pages (from-to)55395-55408
Number of pages14
JournalOncotarget
Volume7
Issue number34
DOIs
Publication statusPublished - 2016

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Juvenile Myelomonocytic Leukemia
Dermatoglyphics
MicroRNAs
Neoplasms
Therapeutics
Leukemia
Cell Proliferation
Small Untranslated RNA
Mutation
Cytokine Receptors
MAP Kinase Signaling System
Granulocyte-Macrophage Colony-Stimulating Factor
Genes
Hypersensitivity
Up-Regulation
Down-Regulation
Phosphorylation
Gene Expression

Keywords

  • GM-CSF
  • JMML
  • MicroRNA
  • MiR-150
  • STAT5b

ASJC Scopus subject areas

  • Oncology

Cite this

MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment. / Leoncini, Pierpaolo; Bertaina, Alice; Papaioannou, Dimitrios; Flotho, Christian; Masetti, Riccardo; Bresolin, S.; Menna, Giuseppe; Santoro, N.; Zecca, Marco; Basso, Giuseppe; Nigita, Giovanni; Veneziano, Dario; Pagotto, Sara; D'Ovidio, Katia; Rota, Rossella; Dorrance, Adrienne; Croce, Carlo M.; Niemeyer, C. M.; Locatelli, Franco; Garzon, Ramiro.

In: Oncotarget, Vol. 7, No. 34, 2016, p. 55395-55408.

Research output: Contribution to journalArticle

Leoncini, P, Bertaina, A, Papaioannou, D, Flotho, C, Masetti, R, Bresolin, S, Menna, G, Santoro, N, Zecca, M, Basso, G, Nigita, G, Veneziano, D, Pagotto, S, D'Ovidio, K, Rota, R, Dorrance, A, Croce, CM, Niemeyer, CM, Locatelli, F & Garzon, R 2016, 'MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment', Oncotarget, vol. 7, no. 34, pp. 55395-55408. https://doi.org/10.18632/oncotarget.10577
Leoncini, Pierpaolo ; Bertaina, Alice ; Papaioannou, Dimitrios ; Flotho, Christian ; Masetti, Riccardo ; Bresolin, S. ; Menna, Giuseppe ; Santoro, N. ; Zecca, Marco ; Basso, Giuseppe ; Nigita, Giovanni ; Veneziano, Dario ; Pagotto, Sara ; D'Ovidio, Katia ; Rota, Rossella ; Dorrance, Adrienne ; Croce, Carlo M. ; Niemeyer, C. M. ; Locatelli, Franco ; Garzon, Ramiro. / MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment. In: Oncotarget. 2016 ; Vol. 7, No. 34. pp. 55395-55408.
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AU - Bertaina, Alice

AU - Papaioannou, Dimitrios

AU - Flotho, Christian

AU - Masetti, Riccardo

AU - Bresolin, S.

AU - Menna, Giuseppe

AU - Santoro, N.

AU - Zecca, Marco

AU - Basso, Giuseppe

AU - Nigita, Giovanni

AU - Veneziano, Dario

AU - Pagotto, Sara

AU - D'Ovidio, Katia

AU - Rota, Rossella

AU - Dorrance, Adrienne

AU - Croce, Carlo M.

AU - Niemeyer, C. M.

AU - Locatelli, Franco

AU - Garzon, Ramiro

PY - 2016

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N2 - Juvenile myelomonocytic leukemia (JMML) is an aggressive leukemia of early childhood characterized by aberrant proliferation of myelomonocytic cells and hypersensitivity to GM-CSF stimulation. Mutually exclusive mutations in the RAS/ERK pathway genes such as PTPN11, NRAS, KRAS, CBL, or NF1 are found in ~90% of the cases. These mutations give rise to disease at least in part by activating STAT5 through phosphorylation and by promoting cell growth. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression, which are often deregulated in leukemia. However, little is known about their role in JMML. Here, we report distinctive miR expression signatures associated with the molecular subgroups of JMML. Among the downregulated miRs in JMML, miR-150-5p was found to target STAT5b, a gene which is often over-activated in JMML, and contributes to the characteristic aberrant signaling of this disorder. Moreover, loss of miR-150-5p and upregulation of STAT5b expression were also identified in a murine model of JMML. Ectopic overexpression of miR-150-5p in mononuclear cells from three JMML patients significantly decreased cell proliferation. Altogether, our data indicate that miR expression is deregulated in JMML and may play a role in the pathogenesis of this disorder by modulating key effectors of cytokine receptor pathways.

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