Global Identification of the miR-130a targetome in human HSPC Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells have firmly established the existence of shared core stemness properties. However, the discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identify miR-130a as a regulator of hematopoietic stem cell (HSC) self-renewal and lineage differentiation. Integration of mass spectrometry and chimeric AGO2 eCLIP-seq identify TBL1XR1 as a primary miR-130a target. TBL1XR1 loss of function impairs lymphoid differentiation and expands long-term (LT)-HSC. This post-transcriptional regulation by miR-130a is usurped in t(8;21) acute myeloid leukemia (AML). Reduction of miR-130a levels in t(8;21) AML cells results in altered chromatin binding and composition of the AML1-ETO complex, demonstrating that miR-130a is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that comprehensive identification of the miRNA targetome within primary tissue enables the discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.