Poster Presentation 25th Lorne Cancer Conference 2013

Increased Interferon Response Gene Expression During Megakaryocyte Ontogeny: Implications for the Spontaneous Resolution of Down Syndrome Transient Myeloproliferative Disorder (#405)

Andrew J. Woo 1 2 , Karen Wieland 1 , Hui Huang 1 , Thomas E. Akie 1 , Jonghwan Kim 3 , Alan B. Cantor 1
  1. Hematology-Oncology, Children's Hospital Boston/Harvard Medical School, Boston, Massachusetts, United States of America
  2. WAIMR-RPH / University of Western Australia, Perth, WA, Australia
  3. Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, United States of America

Down Syndrome (DS) individuals have increased risk for developing leukaemia1.  About 10% of DS infants are born with a transient myeloproliferative disorder (DS-TMD) and 20-30% of these infants subsequently develop acute megakaryoblastic leukemia (DS-AMKL) later in life. For the rest of DS-TMD infants, the condition spontaneously resolves within the first few months of life. Somatic mutations in GATA1 gene, leading to exclusive production of a short GATA1 isoform (GATA-1s) occur in all cases of DS-TMD and DS-AMKL2. Mice engineered to exclusively produce GATA1s have marked hyperproliferative megakaryocytic progenitor cells (MkP) during yolk sac and fetal liver (FL) haematopoiesis, but not during postnatal bone marrow (BM) haematopoiesis, reflecting the spontaneous resolution of DS-TMD in human3. However, the mechanisms that underlie such developmental stage-specific effects are incompletely understood. In this study, we found striking up regulation of interferon alpha responsive genes in murine BM-MkPs compared to embryonic day E13.5 FL-MkPs in both wild type and GATA1s genetic backgrounds. Exogenous IFN-alpha markedly reduced the hyperproliferation of GATA1s E13.5 fetal liver MkPs. Such antiproliferative effects of IFN-alpha were more profound on MkPs than any other cells in hematopoietic lineage. Conversely, genetic deletion of the alpha/beta  interferon receptor 1 gene (IFNAR1) in GATA1s mice or injection of neutralizing IFN-alpha/beta antibodies increased the proliferation of GATA1s BM-MkPs in-vitro and in-vivo beyond the initial post-natal period. Hence, our data suggest a role for IFN-alpha in stage specific regression of GATA1s MkP during development. We also show IFN-alpha response genes are differentially expressed in BM derived human DS-TMD vs DS-AMKL cells, suggesting potential role for genes in IFN axis in leukemic progression. 

  1. Hitzler JK and Zipursky A., 2005. Origins of leukaemia in children with down syndrome. Nat Rev Cancer, 5(1):11-20
  2. Wechsler J et al., 2002. Acquired mutations in GATA1 in the megakaryoblatic leukemia of Down syndrome. Nat Genet, 32(1):148-52
  3. Li Z et al., 2005. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet, 37(6): 613-9.