title: GFI1(36N) as a therapeutic and prognostic marker for myelodysplastic syndrome.
abstract: Inherited gene variants play an important role in malignant diseases. The transcriptional repressor growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single-nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI1(36N)) and has a prevalence of 3%-5% among Caucasians. Because GFI1 regulates myeloid development, we examined the role of GFI1(36N) on the course of MDS disease. To this end, we determined allele frequencies of GFI1(36N) in four independent MDS cohorts from the Netherlands and Belgium, Germany, the ICGC consortium, and the United States. The GFI1(36N) allele frequency in the 723 MDS patients genotyped ranged between 9% and 12%. GFI1(36N) was an independent adverse prognostic factor for overall survival, acute myeloid leukemia-free survival, and event-free survival in a univariate analysis. After adjustment for age, bone marrow blast percentage, IPSS score, mutational status, and cytogenetic findings, GFI1(36N) remained an independent adverse prognostic marker. GFI1(36S) homozygous patients exhibited a sustained response to treatment with hypomethylating agents, whereas GFI1(36N) patients had a poor sustained response to this therapy. Because allele status of GFI1(36N) is readily determined using basic molecular techniques, we propose inclusion of GFI1(36N) status in future prospective studies for MDS patients to better predict prognosis and guide therapeutic decisions.
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Lacramioara
authors.initials: L
authors.lastname: Botezatu
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Michel
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Hematology and Oncology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: Department of Hematology and Oncology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.affiliation: Department of Hematology and Oncology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van der Reijden
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Marneth
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Bergevoet
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wlodarski
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.affiliation: Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Unnikrishnan
authors.affiliation: Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Dominik
authors.initials: D
authors.lastname: Beck
authors.affiliation: Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Pimanda
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
authors.affiliation: Department of Molecular Medicine, University of Pavia, and Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Medical Department with Focus on Hematology/Oncology Charite Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Le Coutre
authors.affiliation: Medical Department with Focus on Hematology/Oncology Charite Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Jaspal
authors.initials: J
authors.lastname: Kaeda
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Opalka
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Hematopoiesis and Cancer Research Unit, and Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Canada.
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciejewski
authors.affiliation: Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address: Cyrus.Khandanpour@uk-essen.de.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khandanpour
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers; D001853:Bone Marrow / Q000473:pathology; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D010198:Pancytopenia; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D014157:Transcription Factors