Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2

被引：1395

作者：

Nangalia, J. ^{[1
,2
,3
,5
,6
]}

Massie, C. E. ^{[1
,2
,3
,5
]}

Baxter, E. J. ^{[1
,2
,3
]}

Nice, F. L. ^{[1
,2
,3
]}

Gundem, G. ^{[5
]}

Wedge, D. C. ^{[5
]}

Avezov, E. ^{[7
,8
]}

Li, J. ^{[2
,3
]}

Kollmann, K. ^{[1
,2
]}

Kent, D. G. ^{[1
,2
]}

Aziz, A. ^{[1
,2
,3
]}

Godfrey, A. L. ^{[1
,2
,3
,6
]}

Hinton, J. ^{[5
]}

Martincorena, I. ^{[5
]}

Van Loo, P. ^{[5
,15
,16
]}

Jones, A. V. ^{[1
,2
,3
,9
]}

Guglielmelli, P. ^{[17
]}

Tarpey, P. ^{[5
]}

Harding, H. P. ^{[7
,8
]}

Fitzpatrick, J. D. ^{[1
,2
]}

Goudie, C. T. ^{[1
,2
]}

Ortmann, C. A. ^{[1
,2
,3
]}

Loughran, S. J. ^{[1
,2
,3
]}

Raine, K. ^{[5
]}

Jones, D. R. ^{[5
]}

Butler, A. P. ^{[5
]}

Teague, J. W. ^{[5
]}

O'Meara, S. ^{[5
]}

McLaren, S. ^{[5
]}

Bianchi, M. ^{[6
]}

Silber, Y. ^{[1
,2
,3
]}

Dimitropoulou, D. ^{[1
,2
,3
]}

Bloxham, D. ^{[6
,14
]}

Mudie, L. ^{[5
]}

Maddison, M. ^{[5
]}

Robinson, B. ^{[5
]}

Keohane, C. ^{[11
]}

Maclean, C. ^{[6
]}

Hill, K. ^{[10
]}

Orchard, K. ^{[10
]}

Tauro, S. ^{[13
]}

Du, M-Q ^{[4
]}

Greaves, M. ^{[12
]}

Bowen, D.

Huntly, B. J. P. ^{[1
,2
,3
,6
]}

Harrison, C. N. ^{[11
]}

Cross, N. C. P. ^{[9
]}

Ron, D. ^{[7
,8
]}

Vannucchi, A. M. ^{[17
]}

Papaemmanuil, E. ^{[5
]}

机构：

[1] Cambridge Inst Med Res, Cambridge CB2 0XY, England

[2] Wellcome Trust MRC Stem Cell Inst, Cambridge, England

[3] Univ Cambridge, Dept Haematol, Cambridge CB2 1TN, England

[4] Univ Cambridge, Div Mol Histopathol, Dept Pathol, Cambridge CB2 1TN, England

[5] Wellcome Trust Sanger Inst, Cambridge, England

[6] Addenbrookes Hosp, Dept Haematol, Cambridge, England

[7] Univ Cambridge, Metab Res Labs, Cambridge, England

[8] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England

[9] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England

[10] Southampton Univ Hosp, Dept Haematol, Southampton, Hants, England

[11] Guys & St Thomas Natl Hlth Serv Fdn Trust, Guys Hosp, London, England

[12] Inst Canc Res, Div Mol Pathol, Haematooncol Res Unit, London SW3 6JB, England

[13] Ninewells Hosp, Dept Hematol, Dundee DD1 9SY, Scotland

[14] St James Hosp, St James Inst Oncol, Leeds LS9 7TF, W Yorkshire, England

[15] VIB, Dept Human Genet, Louvain, Belgium

[16] Katholieke Univ Leuven, Louvain, Belgium

[17] Univ Florence, Dipartimento Med Sperimentale & Clin, Florence, Italy

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2013年 / 369卷 / 25期

基金：

英国惠康基金; 加拿大健康研究院;

关键词：

TYROSINE KINASE JAK2; POLYCYTHEMIA-VERA; ESSENTIAL THROMBOCYTHEMIA; ACTIVATING MUTATION; EXON-12; MUTATIONS; V617F MUTATION; CALRETICULIN; MECHANISMS; MYELOFIBROSIS; GUIDELINE;

D O I：

10.1056/NEJMoa1312542

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundSomatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. MethodsWe performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. ResultsExome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. ConclusionsSomatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.) The authors show that the diverse mutations in CALR that occur in nonmutated JAK2 myeloproliferative diseases all introduce frameshift mutations that alter the C-terminal part of the protein and affect its distribution within cells. The myeloproliferative neoplasms are chronic myeloid cancers that are characterized by the overproduction of mature blood cells, and that may evolve into acute myeloid leukemia.(1),(2) In addition to chronic myeloid leukemia with the BCR-ABL fusion gene, the three most common myeloproliferative neoplasms are essential thrombocythemia, polycythemia vera, and myelofibrosis. Many patients with a BCR-ABL-negative myeloproliferative neoplasm carry a Janus kinase 2 (JAK2) V617F mutation.(3)-(6) The JAK2 V617F mutation or JAK2 exon 12 mutations are found in most patients with polycythemia vera,(7),(8) whereas the JAK2 V617F mutation is found in only 50 to 60% of ...

引用

页码：2391 / 2405

页数：15

共 41 条

[31] Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts [J].

Papaemmanuil, E. ;

Cazzola, M. ;

Boultwood, J. ;

Malcovati, L. ;

Vyas, P. ;

Bowen, D. ;

Pellagatti, A. ;

Wainscoat, J. S. ;

Hellstrom-Lindberg, E. ;

Gambacorti-Passerini, C. ;

Godfrey, A. L. ;

Rapado, I. ;

Cvejic, A. ;

Rance, R. ;

McGee, C. ;

Ellis, P. ;

Mudie, L. J. ;

Stephens, P. J. ;

McLaren, S. ;

Massie, C. E. ;

Tarpey, P. S. ;

Varela, I. ;

Nik-Zainal, S. ;

Davies, H. R. ;

Shlien, A. ;

Jones, D. ;

Raine, K. ;

Hinton, J. ;

Butler, A. P. ;

Teague, J. W. ;

Baxter, E. J. ;

Score, J. ;

Galli, A. ;

Della Porta, M. G. ;

Travaglino, E. ;

Groves, M. ;

Tauro, S. ;

Munshi, N. C. ;

Anderson, K. C. ;

El-Naggar, A. ;

Fischer, A. ;

Mustonen, V. ;

Warren, A. J. ;

Cross, N. C. P. ;

Green, A. R. ;

Futreal, P. A. ;

Stratton, M. R. ;

Campbell, P. J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 365 (15) :1384-1395

[32] IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms [J].

Pardanani, A. ;

Lasho, T. L. ;

Finke, C. M. ;

Mai, M. ;

McClure, R. F. ;

Tefferi, A. .

LEUKEMIA, 2010, 24 (06) :1146-1151

[33] MPLW515L is anovel somatic activating mutation in myelofibrosis with myeloid metaplasia [J].

Pikman, Yana ;

Lee, Benjamin H. ;

Mercher, Thomas ;

McDowell, Elizabeth ;

Ebert, Benjamin L. ;

Gozo, Maricel ;

Cuker, Adam ;

Wernig, Gerlinde ;

Moore, Sandra ;

Galinsky, Ilene ;

DeAngelo, Daniel J. ;

Clark, Jennifer J. ;

Lee, Stephanie J. ;

Golub, Todd R. ;

Wadleigh, Martha ;

Gilliland, D. Gary ;

Levine, Ross L. .

PLOS MEDICINE, 2006, 3 (07) :1140-1151

[34] Structural and Functional Relationships between the Lectin and Arm Domains of Calreticulin [J].

Pocanschi, Cosmin L. ;

Kozlov, Guennadi ;

Brockmeier, Ulf ;

Brockmeier, Achim ;

Williams, David B. ;

Gehring, Kalle .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (31) :27266-27277

[35] JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis [J].

Scott, Linda M. ;

Tong, Wei ;

Levine, Ross L. ;

Scott, Mike A. ;

Beer, Philip A. ;

Stratton, Michael R. ;

Futreal, P. Andrew ;

Erber, Wendy N. ;

McMullin, Mary Frances ;

Harrison, Claire N. ;

Warren, Alan J. ;

Gilliland, D. Gary ;

Lodish, Harvey F. ;

Green, Anthony R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 356 (05) :459-468

[36]

SONNICHSEN B, 1994, J CELL SCI, V107, P2705

[37] DNMT3A mutations in myeloproliferative neoplasms [J].

Stegelmann, F. ;

Bullinger, L. ;

Schlenk, R. F. ;

Paschka, P. ;

Griesshammer, M. ;

Blersch, C. ;

Kuhn, S. ;

Schauer, S. ;

Doehner, H. ;

Doehner, K. .

LEUKEMIA, 2011, 25 (07) :1217-1219

[38] The landscape of cancer genes and mutational processes in breast cancer [J].

Stephens, Philip J. ;

Tarpey, Patrick S. ;

Davies, Helen ;

Van Loo, Peter ;

Greenman, Chris ;

Wedge, David C. ;

Nik-Zainal, Serena ;

Martin, Sancha ;

Varela, Ignacio ;

Bignell, Graham R. ;

Yates, Lucy R. ;

Papaemmanuil, Elli ;

Beare, David ;

Butler, Adam ;

Cheverton, Angela ;

Gamble, John ;

Hinton, Jonathan ;

Jia, Mingming ;

Jayakumar, Alagu ;

Jones, David ;

Latimer, Calli ;

Lau, King Wai ;

McLaren, Stuart ;

McBride, David J. ;

Menzies, Andrew ;

Mudie, Laura ;

Raine, Keiran ;

Rad, Roland ;

Chapman, Michael Spencer ;

Teague, Jon ;

Easton, Douglas ;

Langerod, Anita ;

Lee, Ming Ta Michael ;

Shen, Chen-Yang ;

Tee, Benita Tan Kiat ;

Huimin, Bernice Wong ;

Broeks, Annegien ;

Vargas, Ana Cristina ;

Turashvili, Gulisa ;

Martens, John ;

Fatima, Aquila ;

Miron, Penelope ;

Chin, Suet-Feung ;

Thomas, Gilles ;

Boyault, Sandrine ;

Mariani, Odette ;

Lakhani, Sunil R. ;

van de Vijver, Marc ;

Van 'tVeer, Laura ;

Foekens, John .

NATURE, 2012, 486 (7403) :400-+

[39]

Vardiman JW., 2008, WHO CLASSIFICATION T

[40] Cancer Genome Landscapes [J].

Vogelstein, Bert ;

Papadopoulos, Nickolas ;

Velculescu, Victor E. ;

Zhou, Shibin ;

Diaz, Luis A., Jr. ;

Kinzler, Kenneth W. .

SCIENCE, 2013, 339 (6127) :1546-1558

← 1 2 3 4 5 →