Cooperativity between miR-125b and Gata1 s in the pathogenesis of Down syndrome-associated myeloid leukemia

Down syndrome-associated myeloid leukemia is characterized by the triad of trisomy 21, fetal origin and mutations in GATA1 (GATA1 s mutations). However, the synergy of trisomy 21 and GATA1 s in disease initiation and progression remains to be understood. Leveraging combined CRISPR-Cas9 genome editing and lentiviral overexpression, we interrogated the interaction of the Gata1 s mutation with different permutations of members of the miR-99a˜125b tricistron (miR-125b-2, miR-99a, let-7c) in murine fetal liver cells. We observed major synergistic effects by the combination of Gata1 s with miR-125b, leading to increased proliferation of immature progenitor cells in vitro and induction of leukemia in both primary and secondary recipients. To obtain molecular insights, an shRNA screening individually probing miR-125b targets, combined with RNA-Seq analysis upon inducible miR-125b expression, uncovered the transcription factor Arid3a as the main miR-125b target involved in this process. In conclusion, we present miR-125b cooperates with Gata1 s – in the fetal context – in enhancing proliferation and transformation of hematopoietic progenitors.