Deciphering the deregulated, complex transcription network in Down syndrome myeloid leukemia

Introduction: Children with Down syndrome (DS) have a high risk to develop myeloid leukemia (ML-DS) and antecedent transient abnormal myelopoiesis (TAM). Mutations in exon 2 of GATA1 (GATA1 s-mutations) are necessary and sufficient to induce TAM in synergy with trisomy 21. In contrast, Gata1 ^Δe2 (Gata1 s) mice crossed with Ts65dn mice, which are trisomic for ˜60% of the genes orthologous to human chromosome 21, do not recapitulate the human phenotype.

Results: We investigated the oncogenic properties of GATA1 s in human fetal (with and without DS), neonatal and adult human hematopoietic stem and progenitor cells. Utilizing a lentiviral CRISPR-Cas9 system, we introduced mutations into GATA1 exon 2 via NHEJ repair mechanisms, likely causing GATA1 s formation. In contrast to mice, we did not observe hyperproliferation of GATA1 s fetal megakaryocytic progenitors. Instead, erythroid differentiation was perturbed with the accumulation of immature erythroid progenitors during the combined megakaryocytic/erythroid in vitro differentiation.

Conclusion: Our results provide important novel insights into the pathogenesis of TAM/ML-DS and point towards species specific differences.