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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1552-1559. Prepublished online as a Blood First Edition Paper on October 16, 2007; DOI 10.1182/blood-2007-08-107946. This Article Full Text (PDF) Supplemental Appendix, Tables and Figures All Versions of this Article: blood-2007-08-107946v1 111/3/1552    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Whitman, S. P Articles by Bloomfield, C. D Search for Related Content PubMed PubMed Citation Articles by Whitman, S. P Articles by Bloomfield, C. D Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 21, 2007 Accepted October 10, 2007 FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications Susan P Whitman*, Amy S Ruppert, Michael D Radmacher, Krzysztof Mrozek, Peter Paschka, Christian Langer, Claudia D Baldus, Jing Wen, Frederick Racke, Bayard L Powell, Jonathan E. Kolitz, Richard A Larson, Michael A. Caligiuri, Guido Marcucci, and Clara D Bloomfield Department of Internal Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH The Cancer and Leukemia Group B (CALGB) Statistical Center, Duke University Medical Center, Durham, NC Department of Microbiology, Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, The Ohio State University, Columbus, OH Department of Hematology and Oncology, Charite University Hospital, Campus Benjamin Franklin, Berlin, Germany Department of Pathology, The Ohio State University, Columbus, OH Section on Hematology-Oncology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC Department of Medicine, North Shore University Hospital, Manhasset, NY Department of Medicine, University of Chicago, Chicago, IL * Corresponding author; email: susan.whitman{at}osumc.edu. The prognostic relevance of FLT3 D835/I836 mutations (FLT3-TKD) in cytogenetically normal acute myeloid leukemia (CN-AML) remains to be established. After excluding patients with FLT3 internal tandem duplications, we compared treatment outcome of 16 de novo CN-AML patients with FLT3-TKD with that of 123 patients with wild-type FLT3 (FLT3-WT), aged <60 years and similarly treated on Cancer and Leukemia Group B protocols. All FLT3-TKD+ patients and 85% of FLT3-WT patients achieved a complete remission (P=.13). Disease-free survival (DFS) of FLT3-TKD+ patients was worse than DFS of FLT3-WT patients (P=.01; estimated 3-year DFS rates, 31% vs 60%, respectively). In a multivariable analysis, FLT3-TKD was associated with worse DFS (P=.02) independent of NPM1 status and percentage of bone marrow blasts. To gain further biological insights, a gene-expression signature differentiating FLT3-TKD+ from FLT3-WT patients was identified. The signature (333 probe sets) included overexpression of VNN1, C3AR1, PTPN6 and multiple other genes involved in monocarboxylate transport activity, and underexpression of genes involved in signal transduction regulation. These associations with outcome, other prognostic markers and the elucidated expression signature enhance our understanding of FLT3-TKD-associated biology and may lead to development of novel therapies that improve clinical outcome of CN-AML patients with FLT3-TKD. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Conflicting data on the prognostic significance of FLT3/TKD mutations in acute myeloid leukemia might be related to the incidence of biallelic disease Adam J. Mead, Rosemary E. Gale, Robert K. Hills, Manu Gupta, Bryan D. Young, Alan K. Burnett, and David C. Linch Blood 2008 112: 444-445. [Full Text] [PDF] Response: Conflicting data on the prognostic significance of FLT3-TKD mutations in cytogenetically normal acute myeloid leukemia (CN-AML) might be related to many factors, including techniques used to detect FLT3-TKD, differences in patient populations studied, and treatment regimens Susan P. Whitman, Guido Marcucci, Amy S. Ruppert, Krzysztof Mrózek, and Clara D. Bloomfield Blood 2008 112: 445. [Full Text] [PDF] This article has been cited by other articles: K. H. Metzeler, A. Dufour, T. Benthaus, M. Hummel, M.-C. Sauerland, A. Heinecke, W. E. Berdel, T. Buchner, B. Wormann, U. Mansmann, et al. ERG Expression Is an Independent Prognostic Factor and Allows Refined Risk Stratification in Cytogenetically Normal Acute Myeloid Leukemia: A Comprehensive Analysis of ERG, MN1, and BAALC Transcript Levels Using Oligonucleotide Microarrays J. Clin. Oncol., October 20, 2009; 27(30): 5031 - 5038. [Abstract] [Full Text] [PDF] C. Langer, G. Marcucci, K. B. Holland, M. D. Radmacher, K. Maharry, P. Paschka, S. P. Whitman, K. Mrozek, C. D. Baldus, R. Vij, et al. Prognostic Importance of MN1 Transcript Levels, and Biologic Insights From MN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., July 1, 2009; 27(19): 3198 - 3204. [Abstract] [Full Text] [PDF] U. Bacher, A. Kohlmann, and T. Haferlach Perspectives of gene expression profiling for diagnosis and therapy in haematological malignancies Brief Funct Genomic Proteomic, May 27, 2009; (2009) elp011v1. [Abstract] [Full Text] [PDF] F. Schneider, E. Hoster, M. Unterhalt, S. Schneider, A. Dufour, T. Benthaus, G. Mellert, E. Zellmeier, S. K. Bohlander, M. Feuring-Buske, et al. NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS) Blood, May 21, 2009; 113(21): 5250 - 5253. [Abstract] [Full Text] [PDF] Z. Li, G. Beutel, M. Rhein, J. Meyer, C. Koenecke, T. Neumann, M. Yang, J. Krauter, N. von Neuhoff, M. Heuser, et al. High-affinity neurotrophin receptors and ligands promote leukemogenesis Blood, February 26, 2009; 113(9): 2028 - 2037. [Abstract] [Full Text] [PDF] O. K. Weinberg, M. Seetharam, L. Ren, K. Seo, L. Ma, J. D. Merker, J. Gotlib, J. L. Zehnder, and D. A. Arber Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system Blood, February 26, 2009; 113(9): 1906 - 1908. [Abstract] [Full Text] [PDF] P. Paschka, G. Marcucci, A. S. Ruppert, S. P. Whitman, K. Mrozek, K. Maharry, C. Langer, C. D. Baldus, W. Zhao, B. L. Powell, et al. Wilms' Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., October 1, 2008; 26(28): 4595 - 4602. [Abstract] [Full Text] [PDF] M. Raghavan, L.-L. Smith, D. M. Lillington, T. Chaplin, I. Kakkas, G. Molloy, C. Chelala, J.-B. Cazier, J. D. Cavenagh, J. Fitzgibbon, et al. Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia Blood, August 1, 2008; 112(3): 814 - 821. [Abstract] [Full Text] [PDF] A. J. Mead, R. E. Gale, R. K. Hills, M. Gupta, B. D. Young, A. K. Burnett, and D. C. Linch Conflicting data on the prognostic significance of FLT3/TKD mutations in acute myeloid leukemia might be related to the incidence of biallelic disease Blood, July 15, 2008; 112(2): 444 - 445. [Full Text] [PDF] S. P. Whitman, G. Marcucci, A. S. Ruppert, K. Mrozek, and C. D. Bloomfield Response: Conflicting data on the prognostic significance of FLT3-TKD mutations in cytogenetically normal acute myeloid leukemia (CN-AML) might be related to many factors, including techniques used to detect FLT3-TKD, differences in patient populations studied, and treatment regimens Blood, July 15, 2008; 112(2): 445 - 445. [Full Text] [PDF] B. Basham, M. Sathe, J. Grein, T. McClanahan, A. D'Andrea, E. Lees, and A. Rascle In vivo identification of novel STAT5 target genes Nucleic Acids Res., June 1, 2008; 36(11): 3802 - 3818. [Abstract] [Full Text] [PDF] C. Langer, M. D. Radmacher, A. S. Ruppert, S. P. Whitman, P. Paschka, K. Mrozek, C. D. Baldus, T. Vukosavljevic, C.-G. Liu, M. E. Ross, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study Blood, June 1, 2008; 111(11): 5371 - 5379. [Abstract] [Full Text] [PDF] T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF]

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