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 6

Expansion of BM Mks in GATA1s mice injected with neutralizing IFN-α/β antibodies.

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Expansion of BM Mks in GATA1s mice injected with neutralizing IFN-α/β an...
(A) Experimental scheme. 4- to 6-week-old GATA1s or age-matched WT mice were injected intraperitoneally with 1 × 104 neutralizing units of anti–IFN-α and anti–IFN-β antibodies each, or an equivalent amount of normal rabbit IgG. 8 days after injection, animals were euthanized, and BM was harvested. (B) Flow cytometric color-contour plots for CD41 staining and forward scatter from whole BM (after red blood cell lysis) from 1 representative experiment. (C) Change in CD41+ cell frequency in mice injected with neutralizing IFN-α/β antibodies versus control IgG (n = 3). Results of 3 independent experiments are shown. (D) Representative vWF immunohistochemical stained sections of femur BM from mice injected 8 days earlier with neutralizing anti–IFN-α/β antibodies or equivalent amounts of control IgG. Scale bar: 1 mm. (E) Quantitation of the data in D, showing the mean number of Mks per 2-mm2 field in 10 randomly selected sections.