title: Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms.
abstract: BACKGROUND
  Aberrant activation of tyrosine kinases, caused by either mutation or gene fusion, is of major importance for the development of many hematologic malignancies, particularly myeloproliferative neoplasms. We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms.
  
  
  METHODS
  To detect genomic copy number changes associated with such fusions, we performed a systematic search in 68 patients using custom designed, targeted, high-resolution array comparative genomic hybridization. Arrays contained 44,000 oligonucleotide probes that targeted 500 genes including all 90 tyrosine kinases plus downstream tyrosine kinase signaling components, other translocation targets, transcription factors, and other factors known to be important for myelopoiesis.
  
  
  RESULTS
  No abnormalities involving tyrosine kinases were detected; however, nine cytogenetically cryptic copy number imbalances were detected in seven patients, including hemizygous deletions of RUNX1 or CEBPA in two cases with atypical chronic myeloid leukemia. Mutation analysis of the remaining alleles revealed non-mutated RUNX1 and a frameshift insertion within CEBPA. A further mutation screen of 187 patients with myelodysplastic/myeloproliferative neoplasms identified RUNX1 mutations in 27 (14%) and CEBPA mutations in seven (4%) patients. Analysis of other transcription factors known to be frequently mutated in acute myeloid leukemia revealed NPM1 mutations in six (3%) and WT1 mutations in two (1%) patients with myelodysplastic/myeloproliferative neoplasms. Univariate analysis indicated that patients with mutations had a shorter overall survival (28 versus 44 months, P=0.019) compared with patients without mutations, with the prognosis for cases with CEBPA, NPM1 or WT1 mutations being particularly poor.
  
  
  CONCLUSIONS
  We conclude that mutations of transcription and other nuclear factors are frequent in myelodysplastic/myeloproliferative neoplasms and are generally mutually exclusive. CEBPA, NPM1 or WT1 mutations may be associated with a poor prognosis, an observation that will need to be confirmed by detailed prospective studies.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.forename: Andrew
authors.initials: A
authors.lastname: Chase
authors.forename: Katerina
authors.initials: K
authors.lastname: Zoi
authors.forename: Katherine
authors.initials: K
authors.lastname: Waghorn
authors.forename: Claire
authors.initials: C
authors.lastname: Hidalgo-Curtis
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Amy
authors.initials: A
authors.lastname: Jones
authors.forename: Francis
authors.initials: F
authors.lastname: Grand
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D018628:Gene Dosage; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D038042:Myelopoiesis / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; D000090243:Nucleophosmin