JAK2(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis.
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.
Hussein
Kais
K
Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany.
Bock
Oliver
O
Theophile
Katharina
K
von Neuhoff
Nils
N
Buhr
Thomas
T
Schlué
Jerome
J
Büsche
Guntram
G
Kreipe
Hans
H
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
D015415:Biomarkers; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2