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

Introduction:

Children with trisomy 21 (Down syndrome, DS) have an increased likelihood to develop transient abnormal myelopoiesis (TAM) and subsequent myeloid leukemia (ML-DS). Both diseases are characterized by mutations in the GATA1 gene resulting in a shorter isoform (GATA1 s). However, the synergy of trisomy 21, and in particular its non-coding genes like the miR-99a˜125b tricistron, and GATA1 s in disease initiation and progression remains to be understood.

Results:

Leveraging combined CRISPR-Cas9 genome editing and lentiviral overexpression, we have interrogated the interaction of the Gata1 s mutation with different miR-99a˜125b miRNA permutations in murine fetal liver cells. We observed major synergistic effects by the combination of the Gata1 s with miR-125b in vitro, which we further validated by inducible expression of miR-125b. Transplantation of fetal liver cells harboring the Gata1 s mutation and overexpressing miR-125b underscored the leukemogenic properties of miR125b. To obtain molecular insights, a shRNA screening individually probing miR125b targets, combined with RNA-Seq, has uncovered the mechanism of this synergistic interaction.

Conclusion:

We present miR-125b as a major contributor of the miR-99a˜125b tricistron to TAM and ML-DS patients and provide novel insights into the synergies with Gata1 s -in the fetal context- in enhancing proliferation and transformation of hematopoietic progenitors.