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

Silvia Nucera, Alice Giustacchini, Francesco Boccalatte, Andrea Calabria, Cristiana Fanciullo, Tiziana Plati, Anna Ranghetti, Jose Manuel Garcia Manteiga, Davide Cittaro, Fabrizio Benedicenti, Eric R. Lechman, John E. Dick, Maurilio Ponzoni, Fabio Ciceri, Eugenio Montini, Bernhard Gentner, Luigi Naldini

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)905-921
Number of pages17
JournalCancer Cell
Volume29
Issue number6
DOIs
Publication statusPublished - Jun 13 2016

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ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Nucera, S., Giustacchini, A., Boccalatte, F., Calabria, A., Fanciullo, C., Plati, T., Ranghetti, A., Garcia Manteiga, J. M., Cittaro, D., Benedicenti, F., Lechman, E. R., Dick, J. E., Ponzoni, M., Ciceri, F., Montini, E., Gentner, B., & Naldini, L. (2016). miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia. Cancer Cell, 29(6), 905-921. https://doi.org/10.1016/j.ccell.2016.05.007