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

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): Silvia Nucera, Alice Giustacchini, Francesco Boccalatte, Andrea Calabria, Cristiana Fanciullo, Tiziana Plati, Anna Ranghetti, Jose Garcia-Manteiga, Davide Cittaro, Fabrizio Benedicenti, Eric R. Lechman, John E. Dick, Maurilio Ponzoni, Fabio Ciceri, Eugenio Montini, Bernhard Gentner, Luigi Naldini
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.

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Teaser

Nucera et al. show that sustained miRNA-126 expression across differentiation stages during murine hematopoiesis results in leukemia. Human B-ALL is also dependent on miRNA-126, which orchestrates an oncogenic program by downregulating p53-dependent pathways and maintaining blasts in a B cell precursor state.


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