title: Disease burden at the progenitor level is a feature of primary myelofibrosis: a multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients.
abstract: OBJECTIVE
  Suppression of normal hematopoiesis by the neoplastic clone (clonal dominance) is a feature of the myeloproliferative neoplasms, but the determinants that predict clonal dominance are unknown. The objective of this study was to identify clinical and laboratory variables that associate with the JAK2 V617F CD34(+) progenitor allele burden and clonal dominance, which was defined by congruence of the JAK2 V617F CD34(+) progenitor and neutrophil allele burdens.
  
  
  METHODS
  A cross-sectional analysis was performed on 164 consecutive JAK2 V617F-positive patients: 30 with essential thrombocytosis (ET), 100 with polycythemia vera (PV), and 34 with myelofibrosis (MF), including 8 post-ET MF and 3 post-PV MF. The JAK2 V617F CD34(+) progenitor and neutrophil allele burdens were measured using an allele-specific, quantitative real-time polymerase chain reaction assay.
  
  
  RESULTS
  After adjusting for genotype, sex, age at diagnosis, and disease duration, disease type was the strongest predictor of clonal dominance, with the odds ratio being nearly 61.9 times higher for MF patients when compared with ET patients (p < 0.001), and 9.7 times higher when compared with PV patients (p = 0.002). Additionally, clonal dominance was associated with a clinical phenotype of an increased spleen size (p = 0.006), increased white blood cell count (p = 0.009), and lower hemoglobin (p < 0.001), even after adjusting for disease type and duration.
  
  
  CONCLUSIONS
  These data indicate that loss of wild-type clones at the progenitor level is a feature of MF (primary MF, post-ET MF, and post-PV MF), presumably due to expansion of the JAK2 V617F clone and that this characteristic is surprisingly independent of JAK2 V617F homozygosity, suggesting that additional genomic lesions may contribute to this unique molecular process that distinguishes MF from ET and PV.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Brady L
authors.initials: BL
authors.lastname: Stein
authors.forename: Donna M
authors.initials: DM
authors.lastname: Williams
authors.forename: Ophelia
authors.initials: O
authors.lastname: Rogers
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Isaacs
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Spivak
authors.forename: Alison R
authors.initials: AR
authors.lastname: Moliterno
mesh_terms: D000328:Adult; D000483:Alleles; D018952:Antigens, CD34 / Q000276:immunology; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D055728:Primary Myelofibrosis / Q000235:genetics / Q000473:pathology*
chemical_list: D018952:Antigens, CD34; C507924:JAK2 protein, human; D053614:Janus Kinase 2