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Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype.  miR-99a/100, let-7 , and  miR-125b  paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that  miR-99a/100∼125b  tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor  HOXA10 . Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that  miR-99a/100, let-7 , and  miR-125b  functionally converge at the combinatorial block of the transforming growth factor β (TGFβ) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes  adenomatous polyposis coli  ( APC )/ APC2  stabilizes active β-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the  miR-99a/100∼125b  tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling