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

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. [Display omitted] •Constitutive miRNA-126 expression in progenitors induces miRNA-addicted leukemia•miRNA-126 targets cell cycle/apoptosis and p53 response genes•miRNA-126 stabilizes B-ALL in a proliferative B cell precursor state•Antagonizing miRNA-126 in human B-ALL reduces disease burden in a xenograft model 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.