title: CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons.
abstract: Calreticulin (CALR) mutations were recently described in JAK2 and MPL unmutated primary myelofibrosis (PMF) and essential thrombocythemia. In the current study, we compared the clinical, cytogenetic and molecular features of patients with PMF with or without CALR, JAK2 or MPL mutations. Among 254 study patients, 147 (58%) harbored JAK2, 63 (25%) CALR and 21 (8.3%) MPL mutations; 22 (8.7%) patients were negative for all three mutations, whereas one patient expressed both JAK2 and CALR mutations. Study patients were also screened for ASXL1 (31%), EZH2 (6%), IDH (4%), SRSF2 (12%), SF3B1 (7%) and U2AF1 (16%) mutations. In univariate analysis, CALR mutations were associated with younger age (P<0.0001), higher platelet count (P<0.0001) and lower DIPSS-plus score (P=0.02). CALR-mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. Spliceosome mutations were infrequent (P=0.0001) in CALR-mutated patients, but no other molecular or cytogenetic associations were evident. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status (P=0.001; HR 3.4 for triple-negative and 2.2 for JAK2-mutated). Triple-negative patients also displayed inferior LFS (P=0.003). The current study identifies 'CALR(-)ASXL1(+)' and 'triple-negative' as high-risk molecular signatures in PMF.
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Lasho
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Finke
authors.affiliation: Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Knudson
authors.affiliation: Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ketterling
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Hanson
authors.affiliation: Division of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Maffioli
authors.affiliation: Division of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Caramazza
authors.affiliation: Division of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Passamonti
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D037282:Calreticulin / Q000235:genetics*; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D053628:Receptors, Thrombopoietin / Q000235:genetics*
chemical_list: D037282:Calreticulin; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D053614:Janus Kinase 2