Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome

被引:34
作者
De Vita, S. [1 ]
Canzonetta, C. [1 ]
Mulligan, C. [1 ]
Delom, F. [1 ]
Groet, J. [1 ]
Baldo, C. [2 ]
Vanes, L. [3 ]
Dagna-Bricarelli, F. [2 ]
Hoischen, A. [4 ]
Veltman, J. [4 ]
Fisher, E. M. C. [5 ]
Tybulewicz, V. L. J. [3 ]
Nizetic, D. [1 ]
机构
[1] Queen Mary Univ London, Blizard Inst Cell & Mol Sci, Barts & London Sch Med & Dent, Ctr Paediat, London, England
[2] Galliera Hosp, Human Genet Lab, Genoa, Italy
[3] MRC Natl Inst Med Res, London, England
[4] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands
[5] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England
关键词
chromosome; 21; trisomy; gene expression; Down's syndrome; leukaemia; mouse models; ACUTE LYMPHOBLASTIC LEUKEMIAS; IN-VITRO DIFFERENTIATION; MEGAKARYOBLASTIC LEUKEMIA; TRANSCRIPTION FACTOR; MOUSE MODEL; MYELOID PROGENITOR; ACQUIRED MUTATIONS; FETAL LIVER; EXPRESSION; TRANSIENT;
D O I
10.1038/onc.2010.351
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Children with Down's syndrome (DS) have 20-50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid lineages foetal haematopoiesis, contributing to the increased risk of both leukaemia types in DS. Oncogene (2010) 29, 6102-6114; doi:10.1038/onc.2010.351; published online 9 August 2010
引用
收藏
页码:6102 / 6114
页数:13
相关论文
共 73 条
[1]   A clonogenic common myeloid progenitor that gives rise to all myeloid lineages [J].
Akashi, K ;
Traver, D ;
Miyamoto, T ;
Weissman, IL .
NATURE, 2000, 404 (6774) :193-197
[2]   Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric oncology group study [J].
Al-Kasim, F ;
Doyle, JJ ;
Massey, GV ;
Weinstein, HJ ;
Zipursky, A .
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 2002, 24 (01) :9-13
[3]   Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome [J].
Alford, Kate A. ;
Slender, Amy ;
Vanes, Lesley ;
Li, Zhe ;
Fisher, Elizabeth M. C. ;
Nizetic, Dean ;
Orkin, Stuart H. ;
Roberts, Irene ;
Tybulewicz, Victor L. J. .
BLOOD, 2010, 115 (14) :2928-2937
[4]   Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study [J].
Bahn, S ;
Mimmack, M ;
Ryan, M ;
Caldwell, MA ;
Jaunlaux, E ;
Starkey, M ;
Svendsen, CN ;
Emson, P .
LANCET, 2002, 359 (9303) :310-315
[5]   Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome [J].
Bercovich, Dani ;
Ganmore, Ithamar ;
Scott, Linda M. ;
Wainreb, Gilad ;
Birger, Yehudit ;
Elimelech, Arava ;
Chen, Shochat ;
Cazzaniga, Giovanni ;
Biondi, Andrea ;
Basso, Giuseppe ;
Cario, Gunnar ;
Schrappe, Martin ;
Stanulla, Martin ;
Strehl, Sabine ;
Haas, Oskar A. ;
Mann, Georg ;
Binder, Vera ;
Borkhardt, Arndt ;
Kempski, Helena ;
Trka, Jan ;
Bielorei, Bella ;
Avigad, Smadar ;
Stark, Batia ;
Smith, Owen ;
Dastugue, Nicole ;
Bourquin, Jean-Pierre ;
Ben Tal, Nir ;
Green, Anthony R. ;
Izraeli, Shai .
LANCET, 2008, 372 (9648) :1484-1492
[6]   High-efficiency recovery of functional hematopoietic progenitor and stem cells from human cord blood cryopreserved for 15 years [J].
Broxmeyer, HE ;
Srour, EF ;
Hangoc, G ;
Cooper, S ;
Anderson, SA ;
Bodine, DM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (02) :645-650
[7]   Haploinsufficiency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo [J].
Cai, ZL ;
de Bruijn, M ;
Ma, XQ ;
Dortland, B ;
Luteijn, T ;
Downing, JR ;
Dzierzak, E .
IMMUNITY, 2000, 13 (04) :423-431
[8]   DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome [J].
Canzonetta, Claudia ;
Mulligan, Claire ;
Deutsch, Samuel ;
Ruf, Sandra ;
O'Doherty, Aideen ;
Lyle, Robert ;
Borel, Christelle ;
Lin-Marq, Nathalie ;
Delom, Frederic ;
Groet, Juergen ;
Schnappauf, Felix ;
De Vita, Serena ;
Averill, Sharon ;
Priestley, John V. ;
Martin, Joanne E. ;
Shipley, Janet ;
Denyer, Gareth ;
Epstein, Charles J. ;
Fillat, Cristina ;
Estivill, Xavier ;
Tybulewicz, Victor L. J. ;
Fisher, Elizabeth M. C. ;
Antonarakis, Stylianos E. ;
Nizetic, Dean .
AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 83 (03) :388-400
[9]   Hematopoietic defects in the Ts1Cje mouse model of Down syndrome [J].
Carmichael, Catherine L. ;
Majewski, Ian J. ;
Alexander, Warren S. ;
Metcalf, Donald ;
Hilton, Douglas J. ;
Hewitt, Chelsee A. ;
Scott, Hamish S. .
BLOOD, 2009, 113 (09) :1929-1937
[10]   Cytogenetic and molecular study of 32 Down syndrome families: potential leukaemia predisposing role of the most proximal segment of chromosome 21q [J].
Cavani, S ;
Perfumo, C ;
Argusti, A ;
Pierluigi, M ;
Perroni, L ;
Scmiegelow, K ;
Petersen, MB ;
Cotter, FE ;
Strigini, P ;
Dagna-Bricarelli, F ;
Nizetic, D .
BRITISH JOURNAL OF HAEMATOLOGY, 1998, 103 (01) :213-216