PURPOSE: To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS: Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays. RESULTS: TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I-risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AML patients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I-risk patients and found distinct mutation-associated microRNA signatures in both ELN groups. CONCLUSION: TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.
PURPOSE: To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS: Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays. RESULTS:TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I-risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AMLpatients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I-risk patients and found distinct mutation-associated microRNA signatures in both ELN groups. CONCLUSION:TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.
Authors: Heiko Becker; Guido Marcucci; Kati Maharry; Michael D Radmacher; Krzysztof Mrózek; Dean Margeson; Susan P Whitman; Yue-Zhong Wu; Sebastian Schwind; Peter Paschka; Bayard L Powell; Thomas H Carter; Jonathan E Kolitz; Meir Wetzler; Andrew J Carroll; Maria R Baer; Michael A Caligiuri; Richard A Larson; Clara D Bloomfield Journal: J Clin Oncol Date: 2009-12-21 Impact factor: 44.544
Authors: José L Donato; Jon Ko; Jeffery L Kutok; Tao Cheng; Taro Shirakawa; Xiao-Quan Mao; David Beach; David T Scadden; Mohamed H Sayegh; Chaker N Adra Journal: J Clin Invest Date: 2002-01 Impact factor: 14.808
Authors: Manuela Ferracin; Barbara Zagatti; Lara Rizzotto; Francesco Cavazzini; Angelo Veronese; Maria Ciccone; Elena Saccenti; Laura Lupini; Andrea Grilli; Cristiano De Angeli; Massimo Negrini; Antonio Cuneo Journal: Mol Cancer Date: 2010-05-26 Impact factor: 27.401
Authors: Claudia D Baldus; Sandya Liyanarachchi; Krzysztof Mrózek; Herbert Auer; Stephan M Tanner; Martin Guimond; Amy S Ruppert; Nehad Mohamed; Ramana V Davuluri; Michael A Caligiuri; Clara D Bloomfield; Albert de la Chapelle Journal: Proc Natl Acad Sci U S A Date: 2004-03-08 Impact factor: 11.205
Authors: Omar Abdel-Wahab; Ann Mullally; Cyrus Hedvat; Guillermo Garcia-Manero; Jay Patel; Martha Wadleigh; Sebastien Malinge; JinJuan Yao; Outi Kilpivaara; Rukhmi Bhat; Kety Huberman; Sabrena Thomas; Igor Dolgalev; Adriana Heguy; Elisabeth Paietta; Michelle M Le Beau; Miloslav Beran; Martin S Tallman; Benjamin L Ebert; Hagop M Kantarjian; Richard M Stone; D Gary Gilliland; John D Crispino; Ross L Levine Journal: Blood Date: 2009-05-06 Impact factor: 22.113
Authors: Anna M Jankowska; Hadrian Szpurka; Ramon V Tiu; Hideki Makishima; Manuel Afable; Jungwon Huh; Christine L O'Keefe; Rebecca Ganetzky; Michael A McDevitt; Jaroslaw P Maciejewski Journal: Blood Date: 2009-04-16 Impact factor: 22.113
Authors: Omar Abdel-Wahab; Taghi Manshouri; Jay Patel; Kelly Harris; Jinjuan Yao; Cyrus Hedvat; Adriana Heguy; Carlos Bueso-Ramos; Hagop Kantarjian; Ross L Levine; Srdan Verstovsek Journal: Cancer Res Date: 2010-01-12 Impact factor: 12.701
Authors: Natalia Meier; Sanja Krpic; Patrick Rodriguez; John Strouboulis; Maria Monti; Jeroen Krijgsveld; Martin Gering; Roger Patient; Arnd Hostert; Frank Grosveld Journal: Development Date: 2006-11-15 Impact factor: 6.868
Authors: Alan H Shih; Yanwen Jiang; Cem Meydan; Kaitlyn Shank; Suveg Pandey; Laura Barreyro; Ileana Antony-Debre; Agnes Viale; Nicholas Socci; Yongming Sun; Alexander Robertson; Magali Cavatore; Elisa de Stanchina; Todd Hricik; Franck Rapaport; Brittany Woods; Chen Wei; Megan Hatlen; Muhamed Baljevic; Stephen D Nimer; Martin Tallman; Elisabeth Paietta; Luisa Cimmino; Iannis Aifantis; Ulrich Steidl; Chris Mason; Ari Melnick; Ross L Levine Journal: Cancer Cell Date: 2015-04-13 Impact factor: 31.743
Authors: Chengli Song; Lina Wang; Xiaoyan Wu; Kai Wang; Dan Xie; Qi Xiao; Songyu Li; Kui Jiang; Lujian Liao; John R Yates; Jiing-Dwan Lee; Qingkai Yang Journal: Cancer Res Date: 2018-05-07 Impact factor: 12.701
Authors: Zejuan Li; Tobias Herold; Chunjiang He; Peter J M Valk; Ping Chen; Vindi Jurinovic; Ulrich Mansmann; Michael D Radmacher; Kati S Maharry; Miao Sun; Xinan Yang; Hao Huang; Xi Jiang; Maria-Cristina Sauerland; Thomas Büchner; Wolfgang Hiddemann; Abdel Elkahloun; Mary Beth Neilly; Yanming Zhang; Richard A Larson; Michelle M Le Beau; Michael A Caligiuri; Konstanze Döhner; Lars Bullinger; Paul P Liu; Ruud Delwel; Guido Marcucci; Bob Lowenberg; Clara D Bloomfield; Janet D Rowley; Stefan K Bohlander; Jianjun Chen Journal: J Clin Oncol Date: 2013-02-04 Impact factor: 44.544