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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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 2

Gene expression analysis of FL-MkPs versus BM-MkPs.

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Gene expression analysis of FL-MkPs versus BM-MkPs. (A) Total number of ...
(A) Total number of genes whose expression changed >4-fold with P < 0.05 among the 3 biologic replicates and were represented by probes on the array comparing FL-MkPs versus BM-MkPs for male WT and GATA1s mice. (B and C) Analysis of gene sets enriched in BM-MkPs relative to FL-MkPs and vice versa from WT mice. Asterisks and bold type denote IFN-α–responsive gene sets. (D and F) GSEA for the combined set of 92 IFN-α–induced genes (Supplemental Table 3 and refs. 44, 45) compared with the differentially expressed genes in BM-MkPs versus FL-MkPs in WT (D) and GATA1s (F) mice. (E and G) Probe set intensities corresponding to each of the 92 genes, compared with intensities of 164 randomly selected probe sets, arranged from highest to lowest from the FL-MkP and BM-MkP datasets in WT (E) and GATA1s (G) mice. (H and I) Validation of differences in IFN-α–responsive gene expression in FL-MkPs versus BM-MkPs by conventional PCR (H) and qRT-PCR (I). Some lanes in H were run on different gels or noncontiguous lanes of the same gel.