IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.
In a multi-institutional collaborative project, 1473 patients with myeloproliferative neoplasms (MPN) were screened for isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations: 594 essential thrombocythemia (ET), 421 polycythemia vera (PV), 312 primary myelofibrosis (PMF), 95 post-PV/ET MF and 51 blast-phase MPN. A total of 38 IDH mutations (18 IDH1-R132, 19 IDH2-R140 and 1 IDH2-R172) were detected: 5 (0.8%) ET, 8 (1.9%) PV, 13 (4.2%) PMF, 1 (1%) post-PV/ET MF and 11 (21.6%) blast-phase MPN (P<0.01). Mutant IDH was documented in the presence or absence of JAK2, MPL and TET2 mutations, with similar mutational frequencies. However, IDH-mutated patients were more likely to be nullizygous for JAK2 46/1 haplotype, especially in PMF (P=0.04), and less likely to display complex karyotype, in blast-phase disease (P<0.01). In chronic-phase PMF, JAK2 46/1 haplotype nullizygosity (P<0.01; hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7-5.2), but not IDH mutational status (P=0.55; HR 1.3, 95% CI 0.5-3.4), had an adverse effect on survival. This was confirmed by multivariable analysis. In contrast, in both blast-phase PMF (P=0.04) and blast-phase MPN (P=0.01), the presence of an IDH mutation predicted worse survival. The current study clarifies disease- and stage-specific IDH mutation incidence and prognostic relevance in MPN and provides additional evidence for the biological effect of distinct JAK2 haplotypes.
Tefferi
A
A
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. tefferi.ayalew@mayo.edu
Lasho
T L
TL
Abdel-Wahab
O
O
Guglielmelli
P
P
Patel
J
J
Caramazza
D
D
Pieri
L
L
Finke
C M
CM
Kilpivaara
O
O
Wadleigh
M
M
Mai
M
M
McClure
R F
RF
Gilliland
D G
DG
Levine
R L
RL
Pardanani
A
A
Vannucchi
A M
AM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001752:Blast Crisis; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011087:Polycythemia Vera / Q000235:genetics*; D016133:Polymerase Chain Reaction; D055728:Primary Myelofibrosis / Q000235:genetics*; D011379:Prognosis; D053628:Receptors, Thrombopoietin / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000235:genetics*; D055815:Young Adult
D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2