Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation
Andrew J. Woo, … , Jonghwan Kim, Alan B. Cantor
Andrew J. Woo, … , Jonghwan Kim, Alan B. Cantor
Published July 1, 2013
Citation Information: J Clin Invest. 2013;123(8):3292-3304. https://doi.org/10.1172/JCI40609.
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Research Article Hematology

Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation

Abstract

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.

Authors

Andrew J. Woo, Karen Wieland, Hui Huang, Thomas E. Akie, Taylor Piers, Jonghwan Kim, Alan B. Cantor

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Figure 5

Enhanced postnatal proliferation of GATA1s-containing Mks in an Ifnar1–/– genetic background.

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Enhanced postnatal proliferation of GATA1s-containing Mks in an Ifnar1–/...
(A–D) Peripheral blood platelet count (A), mean platelet volume (B), red blood cell count (C), and white blood cell count (D) of WT (C57BL/6), Ifnar1–/–, GATA1s, and Ifnar1–/–::GATA1s male mice at 3–4 weeks of age. (E–H) Representative AChE-stained BM CFU-Mk colonies from each mouse genotype at 3–4 weeks of age. Original magnification, ×40. Images of the entire slides are shown at left. Red arrows in H indicate hyperplastic colonies. (I) Quantitation of colony size (mean number of pixels covered by colonies derived from photographs) from 20 randomly selected colonies. (J) Representative flow cytometry plots for BrdU and 7AAD (DNA content stain) of CD41+ gated cells obtained from the BM of 3- to 4-week-old mice of the indicated genotypes. (K) Percent CD41+BrdU+ cells from J (n = 3).