Repression Of Tbl1xr1 By Mir-130a Reinforces The Aberrant Molecular Program In T(8,21) Aml

Deregulation of self-renewal and differentiation programs are central to the pathogenesis of hematologic malignancies. MicroRNAs (miRNAs) represent a large class of post-transcriptional regulators that mediate repression of multiple target mRNAs and are frequently deregulated in acute myeloid leukemia (AML). To identify miRNA(s) that play a functional role in human hematopoiesis, we performed an in vivo competitive repopulation screen in which candidate miRNAs were over-expressed (OE) in human CD34+CD38- umbilical cord blood (CB) cells and subsequently transplanted into immune-deficient mice for 24 weeks. miR-130a was shown to enhance long-term hematopoietic reconstitution and chosen for further investigation. Enforced expression of miR-130a conferred a competitive repopulation advantage and induced an expansion of HSPC in xenograft assays. Secondary transplantation at limiting dilution revealed a 10-fold increase in HSC frequency, consistent with a role of miR-130a in enhancing HSC self-renewal. Label-free semi-quantitative proteomics in human HSPC combined with GSEA identified chromatin remodeling as the most significant pathway repressed by miR-130a. TBL1XR1, a component of the nuclear receptor corepressor (NCoR) complex that mediates the exchange of corepressors for coactivators, and CBFb, the β subunit of RUNX1, were among the most repressed miR-130a targets. Interestingly, interrogation of AML datasets revealed elevated expression of miR-130a in t(8,21) AML characterized by the fusion of AML1(RUNX1) and ETO genes. High miR-130a expression was correlated with poor patient overall survival. AML1-ETO recruits the aforementioned NCoR complex to repress RUNX1 target genes, thus preventing myeloid differentiation. To test whether miR-130a controls the AML1-ETO molecular program via repression of TBL1XR1, we tested the effect of miR-130a knock-down in Kasumi cell line and patient samples with the t(8,21). Notably, miR-130a KD resulted in differentiation of transduced cells and increased protein levels of TBL1XR1. Immunoprecipitation of AML1-ETO following miR-130a KD revealed loss of NCoR and CBFβ. Thus, we have uncovered a novel mechanism whereby elevated expression of miR-130a in t(8,21) AML endows enhanced self-renewal and perpetuates the aberrant molecular programs driven by AML1-ETO through inhibition of TBL1XR1.