Early Lineage Priming by Trisomy of Leads to Myeloproliferation in a Down Syndrome Model

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An excess number of genes in trisomy on human chromosome 21 leads to the development of specific diseases in human Down syndrome. An excess copy of the gene, ERG, an ETS family transcription factor, has been implicated in abnormal blood system development in Down syndrome. In this study we show how trisomy of Erg in a murine Down syndrome model perturbs hematopoietic progenitor cells in a manner similar to that observed in human Down syndrome by inducing gene expression changes and lineage priming in early multi-potential progenitors. We show that the gene expression signature specifically attributable to trisomy of Erg in the murine model is strongly correlated with gene expression changes in human Down syndrome hematopoietic cells. The data suggest that Erg is an important regulator of megakaryocyte-erythroid lineage specification in multipotential hematopoietic cells and that trisomy of Erg in the context of DS prediposes to a transient myeloproliferative disorder and acute megakaryocyte leukaemia in a multi-step model of leukemogenesis.

Vyšlo v časopise: Early Lineage Priming by Trisomy of Leads to Myeloproliferation in a Down Syndrome Model. PLoS Genet 11(5): e32767. doi:10.1371/journal.pgen.1005211
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005211

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1. LEJEUNE J, TURPIN R, GAUTIER M (1959) [Chromosomic diagnosis of mongolism.]. Arch Fr Pediatr 16 : 962–963. 14415503

2. Massey G, Zipursky A, Chang M, Doyle J, Nasim S, et al. (2006) 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. Blood 107 : 4606–4613. 16469874

3. Gamis AS, Smith FO (2012) Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 159 : 277–287. doi: 10.1111/bjh.12041 22966823

4. Malinge S, Ragu C, Della-Valle V, Pisani D, Constantinescu S, et al. (2008) Activating mutations in human acute megakaryoblastic leukemia. Blood 112 : 4220–4226. doi: 10.1182/blood-2008-01-136366 18755984

5. Kiyoi H, Yamaji S, Kojima S, Naoe T (2007) JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults. Leukemia 21 : 574–576. 17252020

6. De Vita S, Mulligan C, McElwaine S, Dagna-Bricarelli F, Spinelli M, et al. (2007) Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome. Br J Haematol 137 : 337–341. 17456055

7. Hama A, Muramatsu H, Makishima H, Sugimoto Y, Szpurka H, et al. (2012) Molecular lesions in childhood and adult acute megakaryoblastic leukaemia. Br J Haematol 156 : 316–325. doi: 10.1111/j.1365-2141.2011.08948.x 22122069

8. Klusmann JH, Reinhardt D, Hasle H, Kaspers GJ, Creutzig U, et al. (2007) Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Down's syndrome. Leukemia 21 : 1584–1587. 17443226

9. Hussein K, Bock O, Theophile K, Schulz-Bischof K, Porwit A, et al. (2009) MPLW515L mutation in acute megakaryoblastic leukaemia. Leukemia 23 : 852–855. doi: 10.1038/leu.2008.371 19194467

10. Malkin D, Brown EJ, Zipursky A (2000) The role of p53 in megakaryocyte differentiation and the megakaryocytic leukemias of Down syndrome. Cancer Genet Cytogenet 116 : 1–5. 10616523

11. Yokoyama T, Toki T, Aoki Y, Kanezaki R, Park MJ, et al. (2012) Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia. Blood 119 : 2608–2611. doi: 10.1182/blood-2010-12-324806 22294728

12. Nikolaev SI, Santoni F, Vannier A, Falconnet E, Giarin E, et al. (2013) Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome. Blood 122 : 554–561. doi: 10.1182/blood-2013-03-491936 23733339

13. Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, et al. (2008) Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 112 : 4507–4511. doi: 10.1182/blood-2008-04-152967 18689547

14. Chou S, Opalinska J, Yao Y, Fernandes M, Kalota A, et al. (2008) Trisomy 21 enhances human fetal erythro-megakaryocytic development. Blood 112 : 4503–4506. doi: 10.1182/blood-2008-05-157859 18812473

15. Roy A, Cowan G, Mead AJ, Filippi S, Bohn G, et al. (2012) Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proc Natl Acad Sci U S A 109 : 17579–17584. doi: 10.1073/pnas.1211405109 23045701

16. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S (2004) Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet 5 : 725–738. 15510164

17. Gardiner K, Fortna A, Bechtel L, Davisson M (2003) Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene 318 : 137–147. 14585506

18. Reeves RH (2006) Down syndrome mouse models are looking up. Trends Mol Med 12 : 237–240. 16677859

19. Malinge S, Izraeli S, Crispino J (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113 : 2619–2628. doi: 10.1182/blood-2008-11-163501 19139078

20. Ng A, Hyland C, Metcalf D, Carmichael C, Loughran S, et al. (2010) Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome. Blood 115 : 3966–3969. doi: 10.1182/blood-2009-09-242107 20007548

21. Loughran S, Kruse E, Hacking D, de Graaf C, Hyland C, et al. (2008) The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol 9 : 810–819. doi: 10.1038/ni.1617 18500345

22. Ng AP, Loughran SJ, Metcalf D, Hyland CD, de Graaf CA, et al. (2011) Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice. Blood 118 : 2454–2461. doi: 10.1182/blood-2011-03-344739 21673349

23. Taoudi S, Bee T, Hilton A, Knezevic K, Scott J, et al. (2011) ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification. Genes Dev 25 : 251–262. doi: 10.1101/gad.2009211 21245161

24. Carmichael CL, Metcalf D, Henley KJ, Kruse EA, Di Rago L, et al. (2012) Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia. Proc Natl Acad Sci U S A 109 : 15437–15442. 22936051

25. Tang JZ, Carmichael CL, Shi W, Metcalf D, Ng AP, et al. (2013) Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia. Proc Natl Acad Sci U S A 110 : 6091–6096. doi: 10.1073/pnas.1304234110 23533276

26. Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, et al. (1997) Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript. Blood 90 : 1192–1199. 9242552

27. Baldus C, Burmeister T, Martus P, Schwartz S, Gokbuget N, et al. (2006) High expression of the ETS transcription factor ERG predicts adverse outcome in acute T-lymphoblastic leukemia in adults. J Clin Oncol 24 : 4714–4720. 16954520

28. Baldus C, Liyanarachchi S, Mrozek K, Auer H, Tanner S, et al. (2004) Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci U S A 101 : 3915–3920. 15007164

29. Marcucci G, Baldus C, Ruppert A, Radmacher M, Mrozek K, et al. (2005) Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. J Clin Oncol 23 : 9234–9242. 16275934

30. Kirsammer G, Jilani S, Liu H, Davis E, Gurbuxani S, et al. (2008) Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 111 : 767–775. 17901249

31. Cairney CJ, Sanguinetti G, Ranghini E, Chantry AD, Nostro MC, et al. (2009) A systems biology approach to Down syndrome: identification of Notch/Wnt dysregulation in a model of stem cells aging. Biochim Biophys Acta 1792 : 353–363. doi: 10.1016/j.bbadis.2009.01.015 19419698

32. Akashi K, Traver D, Miyamoto T, Weissman I (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404 : 193–197. 10724173

33. Ng AP, Kauppi M, Metcalf D, Di Rago L, Hyland CD, et al. (2012) Characterization of thrombopoietin (TPO)-responsive progenitor cells in adult mouse bone marrow with in vivo megakaryocyte and erythroid potential. Proc Natl Acad Sci U S A 109 : 2364–2369. doi: 10.1073/pnas.1121385109 22308484

34. Ng AP, Kauppi M, Metcalf D, Hyland CD, Josefsson EC, et al. (2014) Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation. Proc Natl Acad Sci U S A 111 : 5884–5889. doi: 10.1073/pnas.1404354111 24711413

35. Pronk C, Rossi D, Mansson R, Attema J, Norddahl G, et al. (2007) Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1 : 428–442. doi: 10.1016/j.stem.2007.07.005 18371379

36. Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3. 16646809

37. Majewski I, Ritchie M, Phipson B, Corbin J, Pakusch M, et al. (2010) Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 116 : 731–739. doi: 10.1182/blood-2009-12-260760 20445021

38. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, et al. (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res.

39. Wu D, Lim E, Vaillant F, Asselin-Labat ML, Visvader JE, et al. (2010) ROAST: rotation gene set tests for complex microarray experiments. Bioinformatics 26 : 2176–2182. doi: 10.1093/bioinformatics/btq401 20610611

40. Birger Y, Goldberg L, Chlon TM, Goldenson B, Muler I, et al. (2013) Perturbation of fetal hematopoiesis in a mouse model of Down syndrome's transient myeloproliferative disorder. Blood 122 : 988–998. doi: 10.1182/blood-2012-10-460998 23719302

41. Malinge S, Bliss-Moreau M, Kirsammer G, Diebold L, Chlon T, et al. (2012) Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome. J Clin Invest 122 : 948–962. doi: 10.1172/JCI60455 22354171

42. Hewitt C, Carmichael C, Wilkins E, Cannon P, Pritchard M, et al. (2007) Multiplex ligation-dependent probe amplification (MLPA) genotyping assay for mouse models of down syndrome. Front Biosci 12 : 3010–3016. 17485278

43. Shi W, Oshlack A, Smyth GK (2010) Optimizing the noise versus bias trade-off for Illumina whole genome expression BeadChips. Nucleic Acids Res 38: e204. doi: 10.1093/nar/gkq871 20929874

44. Ritchie ME, Diyagama D, Neilson J, van Laar R, Dobrovic A, et al. (2006) Empirical array quality weights in the analysis of microarray data. BMC Bioinformatics 7 : 261. 16712727

45. Smyth GK, Michaud J, Scott HS (2005) Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics 21 : 2067–2075. 15657102

46. Liao Y, Smyth GK, Shi W (2013) The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Research 41.

47. Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30 : 923–930. doi: 10.1093/bioinformatics/btt656 24227677

48. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26 : 139–140. doi: 10.1093/bioinformatics/btp616 19910308

49. Robinson MD, Oshlack A (2010) A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biology 11.

50. Law CW, Chen YS, Shi W, Smyth GK (2014) voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biology 15.

51. Carmichael CL, Majewski IJ, Alexander WS, Metcalf D, Hilton DJ, et al. (2009) Hematopoietic defects in the Ts1Cje mouse model of Down syndrome. Blood 113 : 1929–1937. doi: 10.1182/blood-2008-06-161422 19109561