[HTML][HTML] Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation

AJ Woo, K Wieland, H Huang, TE Akie… - The Journal of …, 2013 - Am Soc Clin Investig
AJ Woo, K Wieland, H Huang, TE Akie, T Piers, J Kim, AB Cantor
The Journal of clinical investigation, 2013Am Soc Clin Investig
About 10% of Down syndrome (DS) infants are born with a transient myeloproliferative
disorder (DS-TMD) that spontaneously resolves within the first few months of life. About 20%–
30% of these infants subsequently develop acute megakaryoblastic leukemia (DS-AMKL).
Somatic mutations leading to the exclusive production of a short GATA1 isoform (GATA1s)
occur in all cases of DS-TMD and DS-AMKL. Mice engineered to exclusively produce
GATA1s have marked megakaryocytic progenitor (MkP) hyperproliferation during early fetal …
About 10% of Down syndrome (DS) infants are born with a transient myeloproliferative disorder (DS-TMD) that spontaneously resolves within the first few months of life. About 20%–30% of these infants subsequently develop acute megakaryoblastic leukemia (DS-AMKL). Somatic mutations leading to the exclusive production of a short GATA1 isoform (GATA1s) occur in all cases of DS-TMD and DS-AMKL. Mice engineered to exclusively produce GATA1s have marked megakaryocytic progenitor (MkP) hyperproliferation during early fetal liver (FL) hematopoiesis, but not during postnatal BM hematopoiesis, mirroring the spontaneous resolution of DS-TMD. The mechanisms that underlie these developmental stage–specific effects are incompletely understood. Here, we report a striking upregulation of type I IFN–responsive gene expression in prospectively isolated mouse BM- versus FL-derived MkPs. Exogenous IFN-α markedly reduced the hyperproliferation FL-derived MkPs of GATA1s mice in vitro. Conversely, deletion of the α/β IFN receptor 1 (Ifnar1) gene or injection of neutralizing IFN-α/β antibodies increased the proliferation of BM-derived MkPs of GATA1s mice beyond the initial postnatal period. We also found that these differences existed in human FL versus BM megakaryocytes and that primary DS-TMD cells expressed type I IFN–responsive genes. We propose that increased type I IFN signaling contributes to the developmental stage–specific effects of GATA1s and possibly the spontaneous resolution of DS-TMD.
The Journal of Clinical Investigation