Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation.

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.

[1]  Luca Pinello,et al.  Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis. , 2012, Developmental cell.

[2]  A. Rambaldi,et al.  Modern therapy of young and adult Ph-ALL. , 2012, Leukemia supplements.

[3]  E. Lander,et al.  Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. , 2012, The Journal of clinical investigation.

[4]  A. Trumpp,et al.  Proteomic Cornerstones of Hematopoietic Stem Cell Differentiation: Distinct Signatures of Multipotent Progenitors and Myeloid Committed Cells* , 2012, Molecular & Cellular Proteomics.

[5]  R. Gómez,et al.  Expression and functionality of type I interferon receptor in the megakaryocytic lineage , 2011, Journal of thrombosis and haemostasis : JTH.

[6]  M. Sola-Visner,et al.  Neonatal and adult megakaryopoiesis , 2011, Current opinion in hematology.

[7]  Clifford A. Meyer,et al.  Cistrome: an integrative platform for transcriptional regulation studies , 2011, Genome Biology.

[8]  R. Silver,et al.  Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report. , 2011, Blood.

[9]  S. Orkin,et al.  Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. , 2010, Genes & development.

[10]  Andreas Trumpp,et al.  IFNα activates dormant haematopoietic stem cells in vivo , 2009, Nature.

[11]  S. Chevret,et al.  Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. , 2008, Blood.

[12]  D. Reinhardt,et al.  Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. , 2008, Blood.

[13]  M. Weiss,et al.  STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. , 2007, The Journal of clinical investigation.

[14]  David Bryder,et al.  Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. , 2007, Cell stem cell.

[15]  M. Talpaz,et al.  The role of interferon-alpha in the treatment of chronic myeloid leukemia. , 2007, Cytokine & growth factor reviews.

[16]  Y. Deyama,et al.  Toll-like receptor 3 ligand-induced antiviral response in mouse osteoblastic cells. , 2007, International journal of molecular medicine.

[17]  A. F. Cunha,et al.  An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis , 2006, Nature Genetics.

[18]  John J Doyle,et al.  A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. , 2006, Blood.

[19]  Aravind Subramanian,et al.  Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Crispino,et al.  Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development. , 2005, Blood.

[22]  S. Orkin,et al.  Developmental stage–selective effect of somatically mutated leukemogenic transcription factor GATA1 , 2005, Nature Genetics.

[23]  D. Reinhardt,et al.  Immunophenotype of Down Syndrome Acute Myeloid Leukemia and Transient Myeloproliferative Disease Differs Significantly from Other Diseases with Morphologically Identical or Similar Blasts , 2005, Klinische Padiatrie.

[24]  C. Haanen,et al.  Recombinant interferon-alpha, but not interferon-gamma is effective therapie for essential thrombocythemia , 2005, Blut.

[25]  T. Toki,et al.  The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome. , 2004, Blood.

[26]  P. Vyas,et al.  Natural history of GATA1 mutations in Down syndrome. , 2004, Blood.

[27]  A. Teigler‐Schlegel,et al.  Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. , 2003, Blood.

[28]  S. Scherer,et al.  GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. , 2003, Blood.

[29]  R. Arceci,et al.  Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. , 2003, Blood.

[30]  D. Nižetić,et al.  Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder , 2003, The Lancet.

[31]  M. L. Beau,et al.  Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome , 2002, Nature Genetics.

[32]  Kozo Nakamura,et al.  RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β , 2002, Nature.

[33]  H. Cai,et al.  Interferon-α activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes , 2002 .

[34]  Thomas Shenk,et al.  Altered Cellular mRNA Levels in Human Cytomegalovirus-Infected Fibroblasts: Viral Block to the Accumulation of Antiviral mRNAs , 2001, Journal of Virology.

[35]  Y. Miyakawa,et al.  Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. , 2000, Blood.

[36]  S. Orkin,et al.  Consequences of GATA-1 Deficiency in Megakaryocytes and Platelets , 1999 .

[37]  A. Zipursky,et al.  Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome. , 1999, Clinics in laboratory medicine.

[38]  S. Orkin,et al.  A lineage‐selective knockout establishes the critical role of transcription factor GATA‐1 in megakaryocyte growth and platelet development , 1997, The EMBO journal.

[39]  G R Stark,et al.  Formation of STAT1-STAT2 Heterodimers and Their Role in the Activation of IRF-1 Gene Transcription by Interferon- (*) , 1996, The Journal of Biological Chemistry.

[40]  T. Toki,et al.  Expression of erythroid‐specific genes in acute megakaryoblastic leukaemia and transient myeloproliferative disorder in Down's syndrome , 1995, British journal of haematology.

[41]  J. Harousseau,et al.  Clonal Hematologic Disorders in Down Syndrome A Review , 1995, Journal of pediatric hematology/oncology.

[42]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[43]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[44]  T. Taniguchi,et al.  Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development , 1993, Cell.

[45]  L. Robison.  Down syndrome and leukemia. , 1992, Leukemia.

[46]  C. Haanen,et al.  Recombinant Interferon-α, but not Interferon-γ, is Effective Therapy for Essential Thrombocythemia , 1990 .

[47]  A. Zipursky,et al.  Megakaryoblastic leukemia and Down's syndrome--a review. , 1987, Progress in clinical and biological research.