title: JAK2(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis.
abstract: OBJECTIVE
  Among Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-) MPN), essential thrombocythemia (ET) and the prefibrotic phase of primary myelofibrosis (PMF) represent two subtypes with considerable overlap.
  
  
  METHODS
  In this study, histopathological classification of 490 MPN cases was correlated with the allelic burden of JAK2(V617F) and MPL(W515L).
  
  
  RESULTS
  Ph(-) MPN entities largely overlap with regard to JAK2(V617F) and MPL(W515L) allele burden, but ET displayed mutant allele burden <50%. PMF with different stages of myelofibrosis all yielded similar JAK2(V617F) allele burden. At initial presentation one-quarter of prefibrotic PMF cases exhibited an allele burden exceeding 50% (38% median JAK2(V617F) alleles, n=102). In ET, its main differential diagnosis, not a single case was found with >40% JAK2(V617F) alleles (median, 24% JAK2(V617F) alleles; n=90; p<0.001). Increase in JAK2(V617F) alleles during follow-up could not be linked to fibrosis or blastic progression but was related to polycythemic transformation in ET. MPL(W515L) was found in 3% of ET and 8% of PMF, with a significantly higher percentage of mutated alleles in fibrotic than prefibrotic PMF (median, 78% MPL(W515L) alleles; p<0.05).
  
  
  CONCLUSIONS
  Histopathological categories ET and prefibrotic PMF correlate with significant differences in mutant allelic burden of JAK2(V617F), but not of MPL(W515L) which, by contrast to JAK2(V617F), shows a higher percentage of mutated alleles in fibrotic than in prefibrotic cases. Thus, for Ph(-) MPN in which ET and prefibrotic PMF represent the most probable diagnoses, a JAK2(V617F) allele burden >50% favors a diagnosis of prefibrotic PMF.
authors.affiliation: Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Kais
authors.initials: K
authors.lastname: Hussein
authors.forename: Oliver
authors.initials: O
authors.lastname: Bock
authors.forename: Katharina
authors.initials: K
authors.lastname: Theophile
authors.forename: Nils
authors.initials: N
authors.lastname: von Neuhoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Buhr
authors.forename: Jerome
authors.initials: J
authors.lastname: Schlué
authors.forename: Guntram
authors.initials: G
authors.lastname: Büsche
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
mesh_terms: D000483:Alleles; D015415:Biomarkers; D001853:Bone Marrow / Q000473:pathology; D003937:Diagnosis, Differential; D018450:Disease Progression; D005355:Fibrosis; D005500:Follow-Up Studies; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D020125:Mutation, Missense; D017354:Point Mutation; D011087:Polycythemia Vera / Q000145:classification / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D055728:Primary Myelofibrosis / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D053628:Receptors, Thrombopoietin / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology
chemical_list: D015415:Biomarkers; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2