A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies

Science Translational Medicine

Volumn 8, Issue 328, 2016, Pages

  Turro, Ernest ^a,b,c,d   Greene, Daniel ^a,c,d   Wijgaerts, Anouck ^e   Thys, Chantal ^e   Lentaigne, Claire ^f,g   Bariana, Tadbir K ^h,i   Westbury, Sarah K ^j   Kelly, Anne M ^a,b   Selleslag, Dominik ^k   Stephens, Jonathan C ^a,b,d   Papadia, Sofia ^a,d   Simeoni, Ilenia ^a,d   Penkett, Christopher J ^a,d   Ashford, Sofie ^a,d   Attwood, Antony ^a,b,d   Austin, Steve ^l   Bakchoul, Tamam ^m   Collins, Peter ⁿ   Deevi, Sri V V ^a,d   Favier, Rémi ^o,p   Kostadima, Myrto ^a,b   Lambert, Michele P ^q,r   Mathias, Mary ^s   Millar, Carolyn M ^f,g   Peerlinck, Kathelijne ^e   Perry, David J ^t   Schulman, Sol ^u   Whitehorn, Deborah ^a,b   Wittevrongel, Christine ^e   De Maeyer, Marc ^v   Rendon, Augusto ^a,w   Gomez, Keith ^h,i   Erber, Wendy N ^x   Mumford, Andrew D ^j   Nurden, Paquita ^y   Stirrups, Kathleen ^a,d   Bradley, John R ^d   Raymond, F Lucy ^d,z   Laffan, Michael A ^f,g   Van Geet, Chris ^e   Richardson, Sylvia ^c   Freson, Kathleen ^e   Ouwehand, H ^a,b,d,aa   more..

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b NHS BLOOD AND TRANSPLANT   (United Kingdom)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^d CAMBRIDGE UNIVERSITY HOSPITALS NHS FOUNDATION TRUST   (United Kingdom)

^e UNIVERSITY OF LEUVEN   (Belgium)

^f IMPERIAL COLLEGE LONDON   (United Kingdom)

^g IMPERIAL COLLEGE HEALTHCARE NHS TRUST   (United Kingdom)

^h UNIVERSITY COLLEGE LONDON   (United Kingdom)

ⁱ ROYAL FREE LONDON NHS FOUNDATION TRUST   (United Kingdom)

^j UNIVERSITY OF BRISTOL   (United Kingdom)

^k Academisch Ziekenhuis Sint Jan   (Belgium)

^l GUY'S AND ST THOMAS' NHS FOUNDATION TRUST   (United Kingdom)

^m UNIVERSITY MEDICINE GREIFSWALD   (Germany)

ⁿ CARDIFF UNIVERSITY   (United Kingdom)

^o ARMAND TROUSSEAU HOSPITAL   (France)

^p Universite Paris Sud   (France)

^q CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^r UNIVERSITY OF PENNSYLVANIA   (United States)

^s GREAT ORMOND STREET HOSPITAL   (United Kingdom)

^t ADDENBROOKE S HOSPITAL   (United Kingdom)

^u HARVARD MEDICAL SCHOOL   (United States)

^v UNIVERSITY OF LEUVEN   (Belgium)

^w GENOMICS ENGLAND   (United Kingdom)

^x UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^y Bordeaux Segalen University   (France)

^z UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^aa WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ACTIN; LENTIVIRUS VECTOR; PROTEIN TYROSINE KINASE; TYROSINE;

AMINO ACID SUBSTITUTION; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BLEEDING; BONE DISEASE; BONE MARROW CELL; CELL CULTURE; CELL GROWTH; CONTROLLED STUDY; COS 7 CELL LINE; DISEASE SEVERITY; EMBRYO; ENZYME ACTIVITY; ENZYME INHIBITION; GAIN OF FUNCTION MUTATION; GENE EXPRESSION; GENE ONTOLOGY; GENE OVEREXPRESSION; GENETIC TRANSDUCTION; HUMAN; HUMAN CELL; IN VITRO STUDY; MEGAKARYOCYTE; MYELODYSPLASTIC SYNDROME; MYELOFIBROSIS; NONHUMAN; ONCOGENE SRC; PATHOGENESIS; PEDIGREE ANALYSIS; PHENOTYPE; PODOSOME; PREDICTION; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SEQUENCE ANALYSIS; STEM CELL; THROMBOCYTOPENIA; THROMBOCYTOPOIESIS; ZEBRA FISH; ANIMAL; BONE; CHLOROCEBUS AETHIOPS; COMPLICATION; COS CELL LINE; FEMALE; GENETIC TRANSFECTION; GENETICS; HEMATOPOIESIS; MALE; MUTATION; MYELOID METAPLASIA; PATHOLOGY; PEDIGREE; THROMBOCYTE;

ANIMALS; BLOOD PLATELETS; BONE AND BONES; CERCOPITHECUS AETHIOPS; COS CELLS; FEMALE; HEMATOPOIESIS; HEMORRHAGE; HUMANS; MALE; MUTATION; PEDIGREE; PHENOTYPE; PRIMARY MYELOFIBROSIS; SRC-FAMILY KINASES; THROMBOCYTOPENIA; TRANSFECTION; ZEBRAFISH;

EID: 84959502592     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aad7666     Document Type: Article

References (59)

1. P. Rous, A transmissible avian neoplasm. (sarcoma of the common fowl.). J. Exp. Med. 12, 696-705 (1910).
2. P. Rous, A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 13, 397-411 (1911).
3. T. Hunter, Discovering the first tyrosine kinase. Proc. Natl. Acad. Sci. U.S.A. 112, 7877-7882 (2015).
4. W.-T. Chen, Proteolytic activity of specialized surface protrusions formed at rosette contact sites of transformed cells. J. Exp. Zool. 251, 167-185 (1989).
5. D. A. Murphy, S. A. Courtneidge, The 'ins' and 'outs' of podosomes and invadopodia: Characteristics, formation and function. Nat. Rev. Mol. Cell Biol. 12, 413-426 (2011).
6. R. B. Irby, W. Mao, D. Coppola, J. Kang, J. M. Loubeau, W. Trudeau, R. Karl, D. J. Fujita, R. Jove, T. J. Yeatman, Activating SRC mutation in a subset of advanced human colon cancers. Nat. Genet. 21, 187-190 (1999).
7. T. J. Yeatman, A renaissance for SRC. Nat. Rev. Cancer 4, 470-480 (2004).
8. G. S. Martin, The hunting of the Src. Nat. Rev. Mol. Cell Biol. 2, 467-475 (2001).
9. M. Breccia, G. Alimena, Second-generation tyrosine kinase inhibitors (Tki) as salvage therapy for resistant or intolerant patients to prior TKIs. Mediterr. J. Hematol. Infect. Dis. 6, e2014003 (2014).
10. H. M. Kantarjian, N. P. Shah, J. E. Cortes, M. Baccarani, M. B. Agar-wal, M. S. Undurraga, J. Wang, J. J. K. Ipiña, D.-W. Kim, M. Ogura, C. Pavlovsky, C. Junghanss, J. H. Milone, F. E. Nicolini, T. Robak, J. Van Droogenbroeck, E. Vellenga, M. B. Bradley-Garelik, C. Zhu, A. Hochhaus, Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-Year follow-up from a randomized phase 3 trial (DASISION). Blood 119, 1123-1129 (2012).
11. A. Golden, S. P. Nemeth, J. S. Brugge, Blood platelets express high levels of the pp60c-srcspecific tyrosine kinase activity. Proc. Natl. Acad. Sci. U.S.A. 83, 852-856 (1986).
12. J. B. Levy, T. Dorai, L. H. Wang, J. S. Brugge, The structurally distinct form of pp60c-src detected in neuronal cells is encoded by a unique c-src mRNA. Mol. Cell. Biol. 7, 4142-4145 (1987).
13. P. Soriano, C. Montgomery, R. Geske, A. Bradley, Targeted disruption of the c-src protooncogene leads to osteopetrosis in mice. Cell 64, 693-702 (1991).
14. Y. A. Senis, A. Mazharian, J. Mori, Src family kinases: At the forefront of platelet activation. Blood 124, 2013-2024 (2014).
15. S. K. Westbury, E. Turro, D. Greene, C. Lentaigne, A. M. Kelly, T. K. Bariana, I. Simeoni, X. Pillois, A. Attwood, S. Austin, S. B. G. Jansen, T. Bakchoul, A. Crisp-Hihn, W. N. Erber, R. Favier, N. Foad, M. Gattens, J. D. Jolley, R. Liesner, S. Meacham, C. M. Millar, A. T. Nurden, K. Peerlinck, D. J. Perry, P. Poudel, S. Schulman, H. Schulze, J. C. Stephens, B. Furie, P. N. Robinson, C. Van Geet, A. Rendon, K. Gomez, M. A. Laffan, M. P. Lambert, P. Nurden, W. H. Ouwehand, S. Richardson, A. D. Mumford, K. Freson; BRIDGE-BPD Consortium, Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders. Genome Med. 7, 36 (2015).
16. S. Köhler, M. H. Schulz, P. Krawitz, S. Bauer, S. Dölken, C. E. Ott, C. Mundlos, D. Horn, S. Mundlos, P. N. Robinson, Clinical diagnostics in human genetics with semantic similarity searches in ontologies. Am. J. Hum. Genet. 85, 457-464 (2009).
17. P. N. Robinson, S. Köhler, A. Oellrich; Sanger Mouse Genetics Project, K. Wang, C. J. Mungall, S. E. Lewis, N. Washington, S. Bauer, D. Seelow, P. Krawitz, C. Gilissen, M. Haendel, D. Smedley, Improved exome prioritization of disease genes through cross-species phenotype comparison. Genome Res. 24, 340-348 (2014).
18. F. Lazner, M. Gowen, D. Pavasovic, I. Kola, Osteopetrosis and osteoporosis: Two sides of the same coin. Hum. Mol. Genet. 8, 1839-1846 (1999).
19. M. Kircher, D. M.Witten, P. Jain, B. J. O'Roak, G.M. Cooper, J. Shendure, A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310-315 (2014).
20. L. Chen, M. Kostadima, J. H. A. Martens, G. Canu, S. P. Garcia, E. Turro, K. Downes, I. C.Macaulay, E. Bielczyk-Maczynska, S. Coe, S. Farrow, P. Poudel, F. Burden, S. B. G. Jansen, W. J. Astle, A. Attwood, T. Bariana, B. De Bono, A. Breschi, J. C. Chambers; BRIDGE Consortium, F. A. Choudry, L. Clarke, P. Coupland, M. Van der Ent, W. N. Erber, J. H. Jansen, R. Favier, M. E. Fenech, N. Foad, K. Freson, C. Van Geet, K. Gomez, R. Guigo, D. Hampshire, A. M. Kelly, H. H. D. Kerstens, J. S. Kooner, M. Laffan, C. Lentaigne, C. Labalette, T. Martin, S. Meacham, A. Mumford, S. Nürnberg, E. Palumbo, B. A. Van der Reijden, D. Richardson, S. J. Sammut, G. Slodkowicz, A. U. Tamuri, L. Vasquez, K. Voss, S. Watt, S. Westbury, P. Flicek, R. Loos, N. Goldman, P. Bertone, R. J. Read, S. Richardson, A. Cvejic, N. Soranzo, W. H. Ouwehand, H. G. Stunnenberg, M. Frontini, A. Rendon, Transcriptional diversity during lineage commitment of human blood progenitors. Science 345, 1251033 (2014).
21. C. A. Albers, A. Cvejic, R. Favier, E. E. Bouwmans, M.-C. Alessi, P. Bertone, G. Jordan, R. N. W. Kettleborough, G. Kiddle, M. Kostadima, R. J. Read, B. Sipos, S. Sivapalaratnam, P. A. Smethurst, J. Stephens, K. Voss, A. Nurden, A. Rendon, P. Nurden, W. H. Ouwehand, Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat. Genet. 43, 735-737 (2011).
22. J. A. Guerrero, C. Bennett, L. Van der Weyden, H. McKinney, M. Chin, P. Nurden, Z. McIntyre, E. L. Cambridge, J. Estabel, H. Wardle-Jones, A. O. Speak, W. N. Erber, A. Rendon, W. H. Ouwehand, C. Ghevaert, Gray platelet syndrome: Proinflammatory megakaryocytes and a-granule loss cause myelofibrosis and confer metastasis resistance in mice. Blood 124, 3624-3635 (2014).
23. G. M. Cooper, E. A. Stone, G. Asimenos, E. D. Green, S. Batzoglou, A. Sidow, Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 15, 901-913 (2005).
24. S. W. Cowan-Jacob, G. Fendrich, P. W. Manley, W. Jahnke, D. Fabbro, J. Liebetanz, T. Meyer, The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. Structure 13, 861-871 (2005).
25. M. K. Ayrapetov, Y.-H. Wang, X. Lin, X. Gu, K. Parang, G. Sun, Conformational basis for SH2-Tyr(P)527 binding in Src inactivation. J. Biol. Chem. 281, 23776-23784 (2006).
26. P. Durek, C. Schudoma, W. Weckwerth, J. Selbig, D. Walther, Detection and characterization of 3D-signature phosphorylation site motifs and their contribution towards improved phosphorylation site prediction in proteins. BMC Bioinf. 10, 117 (2009).
27. P. Patwardhan, M. D. Resh, Myristoylation and membrane binding regulate c-Src stability and kinase activity. Mol. Cell. Biol. 30, 4094-4107 (2010).
28. R. J. Boerner, D. B. Kassel, S. C. Barker, B. Ellis, P. DeLacy, W. B. Knight, Correlation of the phosphorylation states of pp60c-src with tyrosine kinase activity: The intramolecular pY530-SH2 complex retains significant activity if Y419 is phosphorylated. Biochemistry 35, 9519-9525 (1996).
29. F. Wendling, E. Maraskovsky, N. Debili, C. Florindo, M. Teepe, M. Titeux, N. Methia, J. Breton-Gorius, D. Cosman, W. Vainchenker, cMpl ligand is a humoral regulator of megakaryocytopoiesis. Nature 369, 571-574 (1994).
30. M. Ballmaier, M. Germeshausen, H. Schulze, K. Cherkaoui, S. Lang, A. Gaudig, S. Krukemeier, M. Eilers, G. Strauß, K. Welte, c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood 97, 139-146 (2001).
31. M. C. Frame, V. J. Fincham, N. O. Carragher, J. A. Wyke, v-SRC'S hold over actin and cell adhesions. Nat. Rev. Mol. Cell Biol. 3, 233-245 (2002).
32. L. C. Kelley, K. E. Hayes, A. G. Ammer, K. H. Martin, S. A. Weed, Revisiting the ERK/Src cortactin switch. Commun. Integr. Biol. 4, 205-207 (2011).
33. K. Freson, A. Wijgaerts, C. Van Geet, Update on the causes of platelet disorders and functional consequences. Int. J. Lab. Hematol. 36, 313-325 (2014).
34. H. Schachtner, S. D. J. Calaminus, S. G. Thomas, L. M. Machesky, Podosomes in adhesion, migration, mechanosensing and matrix remodeling. Cytoskeleton 70, 572-589 (2013).
35. S. Linder, H. Higgs, K. Hüfner, K. Schwarz, U. Pannicke, M. Aepfelbacher, The polarization defect of Wiskott-Aldrich syndrome macrophages is linked to dislocalization of the Arp2/3 complex. J. Immunol. 165, 221-225 (2000).
36. A. Olivier, L. Jeanson-Leh, G. Bouma, D. Compagno, J. Blondeau, K. Seye, S. Charrier, S. Burns, A. J. Thrasher, O. Danos, W. Vainchenker, A. Galy, A partial down-regulation of WASP is sufficient to inhibit podosome formation in dendritic cells. Mol. Ther. 13, 729-737 (2006).
37. S. Sabri, A. Foudi, S. Boukour, B. Franc, S. Charrier, M. Jandrot-Perrus, R. W. Farndale, A. Jalil, M. P. Blundell, E. M. Cramer, F. Louache, N. Debili, A. J. Thrasher, W. Vainchenker, Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment. Blood 108, 134-140 (2006).
38. A. Dovas, D. Cox, Regulation of WASp by phosphorylation: Activation or other functions? Commun. Integr. Biol. 3, 101-105 (2010).
39. H. Schachtner, S. D. J. Calaminus, A. Sinclair, J. Monypenny, M. P. Blundell, C. Leon, T. L. Holyoake, A. J. Thrasher, A. M. Michie, M. Vukovic, C. Gachet, G. E. Jones, S. G. Thomas, S. P. Watson, L. M. Machesky, Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane. Blood 121, 2542-2552 (2013).
40. F. Saltel, A. Chabadel, E. Bonnelye, P. Jurdic, Actin cytoskeletal organisation in osteoclasts: A model to decipher transmigration and matrix degradation. Eur. J. Cell Biol. 87, 459-468 (2008).
41. A. Zambonin-Zallone, A. Teti, A. Carano, P. C. Marchisio, The distribution of podosomes in osteoclasts cultured on bone laminae: Effect of retinol. J. Bone Miner. Res. 3, 517-523 (1988).
42. A. J. Davidson, L. I. Zon, The 'definitive' (and 'primitive') guide to zebrafish hematopoiesis. Oncogene 23, 7233-7246 (2004).
43. H.-F. Lin, D. Traver, H. Zhu, K. Dooley, B. H. Paw, L. I. Zon, R. I. Handin, Analysis of thrombocyte development in CD41-GFP transgenic zebrafish. Blood 106, 3803-3810 (2005).
44. P. Cingolani, A. Platts, L. L. Wang, M. Coon, T. Nguyen, L. Wang, S. J. Land, X. Lu, D. M. Ruden, A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6, 80-92 (2012).
45. P. N. Robinson, S. Köhler, S. Bauer, D. Seelow, D. Horn, S. Mundlos, The Human Phenotype Ontology: A tool for annotating and analyzing human hereditary disease. Am. J. Hum. Genet. 83, 610-615 (2008).
46. J. A. Blake, C. J. Bult, J. T. Eppig, J. A. Kadin, J. E. Richardson, The Mouse Genome Database Group, The Mouse Genome Database: Integration of and access to knowledge about the laboratory mouse. Nucleic Acids Res. 42, D810-D817 (2014).
47. S. Köhler, S. C. Doelken, B. J. Ruef, S. Bauer, N. Washington, M. Westerfield, G. Gkoutos, P. Schofield, D. Smedley, S. E. Lewis, P. N. Robinson, C. J. Mungall, Construction and accessibility of a cross-species phenotype ontology along with gene annotations for biomedical research. F1000Res. 2, 30 (2013).
48. E. Turro, S.-Y. Su, A. Gonçalves, L. J. M. Coin, S. Richardson, A. Lewin, Haplotype and isoform specific expression estimation using multi-mapping RNA-seq reads. Genome Biol. 12, R13 (2011).
49. E. Turro, W. J. Astle, S. Tavaré, Flexible analysis of RNA-seq data using mixed effects models. Bioinformatics 30, 180-188 (2014).
50. M. Di Michele, C. Thys, E. Waelkens, L. Overbergh, W. D'Hertog, C. Mathieu, R. De Vos, K. Peerlinck, C. Van Geet, K. Freson, An integrated proteomics and genomics analysis to unravel a heterogeneous platelet secretion defect. J. Proteomics 74, 902-913 (2011).
51. C. Hermans, C. Wittevrongel, C. Thys, P. A. Smethurst, C. Van Geet, K. Freson, A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder. J. Thromb. Haemost. 7, 1356-1363 (2009).
52. A. Bonnefoy, K. Daenens, H. B. Feys, R. De Vos, P. Vandervoort, J. Vermylen, J. Lawler, M. F. Hoylaerts, Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13. Blood 107, 955-964 (2006).
53. M. A. Seeliger, B. Nagar, F. Frank, X. Cao, M. N. Henderson, J. Kuriyan, c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty. Structure 15, 299-311 (2007).
54. S. Louwette, L. Régal, C. Wittevrongel, C. Thys, G. Vandeweeghde, E. Decuyper, P. Leemans, R. De Vos, C. Van Geet, J. Jaeken, K. Freson, NPC1 defect results in abnormal platelet formation and function: Studies in Niemann-Pick disease type C1 patients and zebrafish. Hum. Mol. Genet. 22, 61-73 (2013).
55. K. Freson, K. Peeters, R. De Vos, C. Wittevrongel, C. Thys, M. F. Hoylaerts, J. Vermylen, C. Van Geet, PACAP and its receptor VPAC1 regulate megakaryocyte maturation: Therapeutic implications. Blood 111, 1885-1893 (2008).
56. A. Ibrahimi, G. Vande Velde, V. Reumers, J. Toelen, I. Thiry, C. Vandeputte, S. Vets, C. Deroose, G. Bormans, V. Baekelandt, Z. Debyser, R. Gijsbers, Highly efficient multicistronic lentiviral vectors with peptide 2A sequences. Hum. Gene Ther. 20, 845-860 (2009).
57. S. Louwette, C. Van Geet, K. Freson, Regulators of G protein signaling: Role in hematopoiesis, megakaryopoiesis and platelet function. J. Thromb. Haemost. 10, 2215-2222 (2012).
58. C. Rooryck, A. Diaz-Font, D. P. S. Osborn, E. Chabchoub, V. Hernandez-Hernandez, H. Shamseldin, J. Kenny, A. Waters, D. Jenkins, A. A. Kaissi, G. F. Leal, B. Dallapiccola, F. Carnevale, M. Bitner-Glindzicz, M. Lees, R. Hennekam, P. Stanier, A. J. Burns, H. Peeters, F. S. Alkuraya, P. L. Beales, Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nat. Genet. 43, 197-203 (2011).
59. D. Bates, M. Mächler, B. M. Bolker, S. C. Walker, Fitting linear mixed-effects models using lme4. J. Stat. Softw. 1-51 (2014).