OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press25310.17650/1818-8346-2017-12-3-8-16HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯCLINICAL AND LABORATORY FEATURES OF ESSENTIAL THROMBOCYTOSIS AND PRIMARY MYELOFIBROSIS DEPENDING ON JAK2 AND CALR1 MUTATION STATUSКЛИНИКО-ЛАБОРАТОРНЫЕ ОСОБЕННОСТИ ЭССЕНЦИАЛЬНОГО ТРОМБОЦИТОЗА И ПЕРВИЧНОГО МИЕЛОФИБРОЗА В ЗАВИСИМОСТИ ОТ МУТАЦИОННОГО СТАТУСА ГЕНОВ JAK2 И CALR1lisinaE. G.ЛисинаЕ. Г.
Russian Federation

9 Moscovskiy prospect, Cheboksary, Chuvash Republic, 428018

Екатерина Геннадьевна Лисина.

428018 Чебоксары, просп. Московский, 9

eglisina@mail.ruSiordiyaN. T.СиордияН. Т.
Russian Federation

2 Akkuratova str., St. Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

ButylinP. A.БутылинП. А.
Russian Federation

2 Akkuratova str., St. Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

SilyutinaA. A.СилютинаА. А.
Russian Federation

2 Akkuratova str., St. Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

MatyukhinaN. M.МатюхинаН. М.
Russian Federation

2 Akkuratova str., St. Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

SenderovaO. M.СендероваО. М.
Russian Federation

100 Yubileyny microrayon, Irkutsk, 664049

664049 Иркутск, м-н Юбилейный, 100

FokinaE. S.ФокинаЕ. С.
Russian Federation

72 Krasnoarmeiskaya str., Kirov, 610027

610027 Киров, ул. Красноармейская, 72

OvsepyanV. A.ОвсепянВ. А.
Russian Federation

72 Krasnoarmeiskaya str., Kirov, 610027

610027 Киров, ул. Красноармейская, 72

LomaiaE. G.ЛомаиаЭ. Г.
Russian Federation

2 Akkuratova str., St. Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

ZaritskiyA. Yu.ЗарицкийА. Ю.
Russian Federation

2 Akkuratova str., St. Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

Chuvash Republican Clinical HospitalРеспубликанская клиническая больница» Минздрава Чувашской РеспубликиAlmazov National Medical Research CenterФГБУ «Национальный медицинский исследовательский центр им. В.А. Алмазова» Минздрава России“Badge of Honor” Irkutsk Regional Clinical HospitalГБУЗ «Иркутская ордена “Знак Почета” областная клиническая больница»Kirov Scientific Research Institute of Hematology and Blood TransfusionФГБУН «Кировский научно-исследовательский институт гематологии и переливания крови Федерального медикобиологического агентства»241020171238162510201725102017https://oncohematology.abvpress.ru/ongm/article/view/253

Introduction. JAK2V617F mutation is detected in approximately 50 % of patients with essential thrombocytosis (ET) and primary myelofibrosis (PMF). In 2013 most of the JAK2 negative patients showed mutations in the CALR gene. Diagnostic value of JAK2 and CALR mutations is high, but their prognostic significance is not sufficiently clear. Data on impact of JAK2 and CALR mutational status on thrombotic complications in ET and myelofibrosis patients are contradictory.

The aim of the study was to identify clinical and laboratory features in patients with ET and PMF in accordance with the mutational status of JAK2V617F and CALR gene.

Materials and methods. Patients treated in Almazov National Medical Research Center (St. Petersburg), Chuvash Republican Clinical Hospital (Cheboksary), Irkutsk Regional Clinical Hospital (Irkutsk),  Kirov Research Institute of Hematology and Blood Transfusion (Kirov) was included in the retrospective study. CALR mutation (1 and 2 types), MPL W515L/K and JAK2V617F mutation were detected in peripheral blood cells.

Results. We identified that 21 % (n = 16) of ET patients had thrombotic complications, and they occurred more often among JAK2V617F positive patients (p <0.05). The median of hemoglobin level in PMF was the lowest in the group of triple negative patients. The level of leukocytes in PMF was higher in the group of triple negative patients than in the group with mutated CALR (p = 0.014).

Conclusion. JAK2V617F mutation in ET patients was associated with a high risk of thrombosis. Patients with CALR mutations may have a favorable prognosis regarding to thrombotic complications. Some laboratory features of CALR mutations in ET and PMF patients have been revealed.

Введение. Мутация гена JAK2V617F встречается примерно у 50 % пациентов с эссенциальным тромбоцитозом (ЭТ) и первичным миелофиброзом (ПМФ). В 2013 г. у большинства JAK2-негативных пациентов выявлены мутации в гене CALR. Диагностическая ценность мутаций в генах JAK2 и CALR высокая, но их прогностическая значимость недостаточно ясна. Данные о влиянии мутационного статуса генов JAK2 и CALR на тромботические осложнения при ЭТ и ПМФ противоречивы.

Цель исследования – выявление клинико-лабораторных особенностей у пациентов с ЭТ и ПМФ в зависимости от наличия мутаций генов JAK2V617F и CALR.

Материалы и методы. Проведено ретроспективное исследование пациентов, наблюдавшихся в четырех медицинских учреждениях Санкт-Петербурга,  Чебоксар, Иркутска  и Кирова (БУ «Республиканская клиническая больница» Минздрава Чувашской Республики, ФГБУ «Национальный медицинский исследовательский центр им. В. А. Алмазова» Минздрава России, ГБУЗ «Иркутская ордена “Знак Почета” областная клиническая больница», ФГБУН «Кировский научно-исследовательский институт гематологии и переливания крови Федерального медико-биологического агентства»). В клетках  периферической крови пациентов проводили определение генетических мутаций: CALR (с выделением 1-го и 2-го типов), MPL W515L/K, JAK2V617F.

Результаты. При ЭТ у 21 % (n = 16) больных зарегистрированы тромботические осложнения, при этом они встречались чаще среди носителей мутации JAK2V617F (p <0,05). При ПМФ медиана уровня гемоглобина оказалась наименьшей в группе пациентов с «тройным негативным» статусом, а уровень лейкоцитов более высоким, чем в группе с мутациями CALR (р = 0,014).

Заключение. При ЭТ мутация JAK2 сопровождается высоким риском развития тромбозов. Наличие мутации CALR может иметь благоприятный прогноз в плане риска развития тромботических осложнений. Выявлены некоторые лабораторные особенности, характерные для мутации CALR при ЭТ и ПМФ.

essential thrombocytosismyelofibrosischronic myeloproliferative diseasesJAK2CALRthrombotic complicationsэссенциальный тромбоцитозмиелофиброзхронические миелопролиферативные заболеванияJAK2CALRтромботические осложненияWork
performed
under
the
state
order
of
Ministry
of
Health
of
Russia
2015-2017
yy.
«Risk-adapted
therapy
approaches
based
on
new
molecular
prognosis
factors
for
lympho-
and
myeloproliferative
diseases»
(platform
«Oncology
and
Radiation
Technologies»)Государственное
задание
Минздрава
России
20152017
гг.
«Рискадаптированные
подходы
к
терапии
на
основе
новых
молекулярных
факторов
прогноза
при
лимфо-
и
миелопролиферативных
заболеваниях»
(платформа
«Онкология
и
радиационные
технологии»)1.
 Baxter
E.J.,
Scott
L.M.,
Campbell
P.J.
et
al.
Acquired
mutation
of
the
tyrosine
kinase
JAK2
in
human
myeloproliferative
disor-ders.
Lancet
2005;365:1054–1056.

DOI:
10.1016/S0140-6736(05)71142-9.
PMID:
15781101.Baxter E.J., Scott L.M., Campbell P.J. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disor-ders. Lancet 2005;365:1054–1056. DOI: 10.1016/S0140-6736(05)71142-9. PMID: 15781101.2.
James
C.,
Ugo
V.,
Le
Couedic
J.P.
et
al.

A
unique
clonal
JAK2
mutation
leading

to
constitutive
signaling
causes
polycythaemia
vera.
Nature
2005;434(7037):1144–1148.
DOI:
10.1038/nature03546.

PMID:
15793561.James C., Ugo V., Le Couedic J.P. et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005;434(7037):1144–1148. DOI: 10.1038/nature03546. PMID: 15793561.3.
 Levine
R.L.,
Wadleigh
M.,
Cools
J.
et
al.
Activating
mutation
in
the
tyrosine
kinase
JAK2
in
polycythemia
vera,
essential
thrombocythemia,
and
myeloid
metaplasia
with
myelofibrosis.
Cancer
Cell
2005;7(4):387–397.
DOI:
10.1016/j.ccr.2005.03.023.
PMID:
15837627.Levine R.L., Wadleigh M., Cools J. et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7(4):387–397. DOI: 10.1016/j.ccr.2005.03.023. PMID: 15837627.4.
 Kralovics
R.,
Passamonti
F.,
Buser
A.S.

et
al.
A
gain-of-function
mutation
of
JAK2
in
myeloproliferative
disorders.
N
Engl
J
Med
2005;352(17):1779–1790.

DOI:
10.1056/NEJMoa051113.

PMID:
15858187.Kralovics R., Passamonti F., Buser A.S. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352(17):1779–1790. DOI: 10.1056/NEJMoa051113. PMID: 15858187.5.
 Levine
R.L.,
Belisle
C.,
Wadleigh
M.
et
al.
X-inactivation-based
clonality
analysis
and
quantitative
JAK2V617F
assessment
reveals
a
strong
association
between
clonality
and
JAK2V617F
in
PV
but
not
ET/MMM,
and
identifies
a
subset
of
JAK2V617F-negative
ET
and
MMM
patients
with
clonal
hema-topoiesis.
Blood
2006;107(10):4139–4141.
DOI:
10.1182/blood-2005-09-3900.
PMID:
16434490.Levine R.L., Belisle C., Wadleigh M. et al. X-inactivation-based clonality analysis and quantitative JAK2V617F assessment reveals a strong association between clonality and JAK2V617F in PV but not ET/MMM, and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hema-topoiesis. Blood 2006;107(10):4139–4141. DOI: 10.1182/blood-2005-09-3900. PMID: 16434490.6.
 Antonioli
E.,
Guglielmelli
P.,
Pancrazzi
A.
et
al.
Clinical
implications
of
the
JAK2
V617F
mutation
in
essential
thrombocythe-mia.
Leukemia
2005;19:1847–1849.

DOI:
10.1038/sj.leu.2403902.

PMID:
16079890.Antonioli E., Guglielmelli P., Pancrazzi A. et al. Clinical implications of the JAK2 V617F mutation in essential thrombocythe-mia. Leukemia 2005;19:1847–1849. DOI: 10.1038/sj.leu.2403902. PMID: 16079890.7.
 Campbell
P.J.,
Scott
L.M.,
Buck
G.
et
al.
Definition
of
subtypes
of
essential
thrombocythaemia
and
relation
to
polycythaemia
vera
based
on
JAK2
V617F
mutation
status:a
prospective
study.
Lancet
2005;366:1945–1953.
DOI:
10.1016/S0140-6736(05)67785-9.
PMID:
16325696.Campbell P.J., Scott L.M., Buck G. et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status:a prospective study. Lancet 2005;366:1945–1953. DOI: 10.1016/S0140-6736(05)67785-9. PMID: 16325696.8.
 Jones
A.V.,
Kreil
S.,
Zoi
K.
et
al.
Widespread
occurrence
of
the
JAK2
V617F
mutation
in
chronic
myeloproliferative
disorders.
Blood
2005;106(6):2162–2168.

DOI:
10.1182/blood-2005-03-1320.
PMID:
15920007.Jones A.V., Kreil S., Zoi K. et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106(6):2162–2168. DOI: 10.1182/blood-2005-03-1320. PMID: 15920007.9.
 Wolanskyj
A.P.,
Lasho
T.L.,
Schwager
S.M.

et
al.
JAK2
mutation
in
essential
thrombocythaemia:
clinical
associations
and
longterm
prognostic
relevance.
Br
J
Haematol
2005;131(2):208–213.
DOI:
10.1111/j.1365-2141.2005.05764.x.
PMID:
16197451.Wolanskyj A.P., Lasho T.L., Schwager S.M. et al. JAK2 mutation in essential thrombocythaemia: clinical associations and longterm prognostic relevance. Br J Haematol 2005;131(2):208–213. DOI: 10.1111/j.1365-2141.2005.05764.x. PMID: 16197451.10.
 Campbell
P.J.,
Griesshammer
M.,
Dohner
K.
et
al.
V617F
mutation
in
JAK2
is
associated
with
poorer
survival
in
idiopathic
myelofibrosis.
Blood
2006;107:2098–2100.

DOI:
10.1182/blood-2005-08-3395.
PMID:
16293597.Campbell P.J., Griesshammer M., Dohner K. et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood 2006;107:2098–2100. DOI: 10.1182/blood-2005-08-3395. PMID: 16293597.11.
 Tefferi
A.,
Lasho
T.L.,
Schwager
S.M.
et
al.
The
JAK2(V617F)
tyrosine
kinase
mutation
in
myelofibrosis
with
myeloid
metaplasia:
lineage
specificity
and
clinical
correlates.

Br
J
Haematol
2005;131(3):320–328.

DOI:
10.1111/j.1365-2141.2005.05776.x.
PMID:
16225651.Tefferi A., Lasho T.L., Schwager S.M. et al. The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol 2005;131(3):320–328. DOI: 10.1111/j.1365-2141.2005.05776.x. PMID: 16225651.12.
 Passamonti
F.,
Elena
C.,
Schnittger
S.
et
al.
Molecular
and
clinical
features
of
the
myeloproliferative
neoplasm
associated
with
JAK2
exon
12
mutations.
Blood
2011;117(10):2813–6.
DOI:
10.1182/blood-2010-11-316810.
PMID:
21224469.Passamonti F., Elena C., Schnittger S. et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood 2011;117(10):2813–6. DOI: 10.1182/blood-2010-11-316810. PMID: 21224469.13.
 Kisseleva
T.,
Bhattacharya
S.,
Braunstein
J.,
Schindler
C.W.
Signaling
through
the
JAK/ STAT
pathway,
recent
advances
and
future
challenges.
Gene
2002;285(1–2):124.
PMID:
12039028.Kisseleva T., Bhattacharya S., Braunstein J., Schindler C.W. Signaling through the JAK/ STAT pathway, recent advances and future challenges. Gene 2002;285(1–2):124. PMID: 12039028.14.
Sandberg
E.M.,
Wallace
T.A.,
Godeny
M.D.
et
al.
Jak2
tyrosine
kinase:
a
true
jak
of
all
trades?
Cell
Biochem
Biophys
2004;41(2):207–232.
PMID:
15475610.Sandberg E.M., Wallace T.A., Godeny M.D. et al. Jak2 tyrosine kinase: a true jak of all trades? Cell Biochem Biophys 2004;41(2):207–232. PMID: 15475610.15.
 Zhao
R.,
Xing
S.,
Li
Z.
et
al.
Identification
of
an
acquired
JAK2
mutation
in
polycythemia
vera.
J
Biol
Chem
2005;280(24):22788–22792.
DOI:
10.1074/jbc.C500138200.
PMID:
15863514.Zhao R., Xing S., Li Z. et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280(24):22788–22792. DOI: 10.1074/jbc.C500138200. PMID: 15863514.16.
 Staerk
J.,
Lacout
C.,
Sato
T.
et
al.
An
amphipathic
motif
at
the
transmembrane-cytoplasmic
junction
prevents
autonomous
activation
of
the
thrombopoietin
receptor.
Blood
2006;107(5):1864–1871.

DOI:
10.1182/blood-2005-06-2600.
PMID:
16249382.Staerk J., Lacout C., Sato T. et al. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood 2006;107(5):1864–1871. DOI: 10.1182/blood-2005-06-2600. PMID: 16249382.17.
 Pikman
Y.,
Lee
B.H.,
Mercher
T.
et
al.
MPLW515L
is
a
novel
somatic
activating
mutation
in
myelofibrosis
with
myeloid
metaplasia.
PLoS
Med
2006;3(7):e270.
DOI:
10.1371/journal.pmed.0030270.
PMID:
16834459.Pikman Y., Lee B.H., Mercher T. et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3(7):e270. DOI: 10.1371/journal.pmed.0030270. PMID: 16834459.18.
 Pardanani
A.D.,
Levine
R.L.,
Lasho
T.

et
al.
MPL515
mutations
in
myeloproliferative
and
other
myeloid
disorders:
a
study

of
1182
patients.
Blood
2006;108(10):3472–6.
DOI:
10.1182/blood-2006-04-018879.
PMID:
16868251.Pardanani A.D., Levine R.L., Lasho T. et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006;108(10):3472–6. DOI: 10.1182/blood-2006-04-018879. PMID: 16868251.19.
 Klampfl
T.,
Gisslinger
H.,
Harutyunyan
A.S.
et
al.
Somatic
Mutations
of
Calreticulin

in
Myeloproliferative
Neoplasms.
N
Engl

J
Med
2013;369(25):2379–2390.

DOI:
10.1056/NEJMoa1311347.

PMID:
24325356.Klampfl T., Gisslinger H., Harutyunyan A.S. et al. Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N Engl J Med 2013;369(25):2379–2390. DOI: 10.1056/NEJMoa1311347. PMID: 24325356.20.
 Nangalia
J.,
Massie
C.E.,
Baxter
E.J.
et
al.
Somatic
CALR
Mutations
in
Myeloproliferative
Neoplasms
with
Nonmutated
JAK2.
N
Engl
J
Med
2013;369(25):2391–2405.
DOI:
10.1056/NEJMoa1312542.

PMID:
24325359.Nangalia J., Massie C.E., Baxter E.J. et al. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. N Engl J Med 2013;369(25):2391–2405. DOI: 10.1056/NEJMoa1312542. PMID: 24325359.21.
 Rumi
E.,
Pietra
D.,
Ferretti
V.
et
al.
Associazione
Italiana
per
la
Ricerca
sul
Cancro
Gruppo
Italiano
Malattie
Mieloproliferative
Investigators.
JAK2
or
CALR
mutation
status
defines
subtypes
of
essential
thrombocythemia
with
substantially
different
clinical
course
and
outcomes.
Blood
2014;123(10):1544–1551.
DOI:
10.1182/blood-2013-11-539098.
PMID:
24366362.Rumi E., Pietra D., Ferretti V. et al. Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014;123(10):1544–1551. DOI: 10.1182/blood-2013-11-539098. PMID: 24366362.22.
 Cabagnols
X.,
Defour
J.P.,
Ugo
V.
et
al.
Differential
association
of
calreticulin
type
1
and
type
2
mutations
with
myelofibrosis
and
essential
thrombocytemia:
relevance
for
disease
evolution.
Leukemia
2015;29:249–252.
DOI:
10.1038/leu.2014.270.
PMID:
25212275.Cabagnols X., Defour J.P., Ugo V. et al. Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution. Leukemia 2015;29:249–252. DOI: 10.1038/leu.2014.270. PMID: 25212275.23.
 Chachoua
I.,
Pecquet
C.,
El-Khoury
M.

et
al.
Thrombopoietin
receptor
activation
by
myeloproliferative
neoplasm
associated
calreticulin
mutants.
Blood
2016;127(10):1325–35.
DOI:
10.1182/blood-2015-11-681932.
PMID:
26668133.Chachoua I., Pecquet C., El-Khoury M. et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood 2016;127(10):1325–35. DOI: 10.1182/blood-2015-11-681932. PMID: 26668133.24.
 Araki
M.,
Yang
Y.,
Masubuchi
N.
et
al.

Activation
of
the
thrombopoietin
receptor
by
mutant
calreticulin
in
CALR-mutant
myeloproliferative
neoplasms.
Blood
2016;127(10):1307–1316.
DOI:
10.1182/blood-2015-09-671172.
PMID:
26817954.Araki M., Yang Y., Masubuchi N. et al. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. Blood 2016;127(10):1307–1316. DOI: 10.1182/blood-2015-09-671172. PMID: 26817954.25.
 Abdel-Wahab
O.,
Manshouri
T.,
Patel
J.

et
al.
Genetic
analysis
of
transforming
events
that
convert
chronic
myeloproliferative
neoplasms
to
leukemias.
Cancer
Res
2010;70(2):447–452.
DOI:
10.1158/0008-5472.CAN-09-3783.
PMID:
20068184.Abdel-Wahab O., Manshouri T., Patel J. et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 2010;70(2):447–452. DOI: 10.1158/0008-5472.CAN-09-3783. PMID: 20068184.26.
 Delhommeau
F.,
Dupont
S.,
Della
Valle
V.
et
al.
Mutation
in
TET2
in
myeloid
cancers.
N
Engl
J
Med
2009;360(22):2289–2301.
DOI:
10.1056/NEJMoa0810069.

PMID:
19474426.Delhommeau F., Dupont S., Della Valle V. et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360(22):2289–2301. DOI: 10.1056/NEJMoa0810069. PMID: 19474426.27.
 Zhang
S.J.,
Rampal
R.,
Manshouri
T.
et
al.
Genetic
analysis
of
patients
with
leukemic
transformation
of
myeloproliferative
neoplasms
shows
recurrent
SRSF2
mutations
that
are
associated
with
adverse
outcome.
Blood
2012;119(19):4480–4485.

DOI:
10.1182/blood-2011-11-390252
PMID:
22431577.Zhang S.J., Rampal R., Manshouri T. et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 2012;119(19):4480–4485. DOI: 10.1182/blood-2011-11-390252 PMID: 22431577.28.
 Tefferi
A.,
Lasho
T.L.,
Finke
C.M.
et
al.
CALR
vs
JAK2
vs
MPL-mutated
or
triplenegative
myelofibrosis:
clinical,
cytogenetic
and
molecular
comparisons.
Leukemia
2014;28(7):1472–1477.
DOI:
10.1038/leu.2014.3.
PMID:
24402162.Tefferi A., Lasho T.L., Finke C.M. et al. CALR vs JAK2 vs MPL-mutated or triplenegative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014;28(7):1472–1477. DOI: 10.1038/leu.2014.3. PMID: 24402162.29.
 Rampal
R.,
Ahn
J.,
Abdel-Wahab
O.
et
al.
Genomic
and
functional
analysis
of
leukemic
transformation
of
myeloproliferative
neoplasms.
Proc
Natl
Acad
Sci
USA
2014;111(50):E5401–E5410.

DOI:
10.1073/pnas.1407792111.

PMID:
25516983.Rampal R., Ahn J., Abdel-Wahab O. et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci USA 2014;111(50):E5401–E5410. DOI: 10.1073/pnas.1407792111. PMID: 25516983.30.
 Skoda
R.C.,
Duek
A.,
Grisouard
J.
Pathogenesis
of
myeloproliferative
neoplasms.

Exp
Hematol
2015;43(8):599–608.

DOI:
10.1016/j.exphem.2015.06.007.
PMID:
26209551.Skoda R.C., Duek A., Grisouard J. Pathogenesis of myeloproliferative neoplasms. Exp Hematol 2015;43(8):599–608. DOI: 10.1016/j.exphem.2015.06.007. PMID: 26209551.31.
 Arber
D.A.,
Orazi
A.,
Hasserjian
R.
et
al.
The
2016
revision
to
the
World
Health
Organization
classification
of
myeloid
neoplasms
and
acute
leukemia.
Blood
2016;127(20):2391–2405.
DOI:
10.1182/blood-2016-03-643544.
PMID:
27069254.Arber D.A., Orazi A., Hasserjian R. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391–2405. DOI: 10.1182/blood-2016-03-643544. PMID: 27069254.32.
 Rumi
E.,
Pietra
D.,
Pascutto
C.
et
al.
Clinical
effect
of
driver
mutations
of
JAK2,
CALR,
or
MPL
in
primary
myelofibrosis.
Blood
2014;124(7):1062–9.
DOI:
10.1182/blood-2014-05-578435.
PMID:
24986690.Rumi E., Pietra D., Pascutto C. et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 2014;124(7):1062–9. DOI: 10.1182/blood-2014-05-578435. PMID: 24986690.33.
 Tefferi
A.,
Wassie
E.A.,
Lasho
T.L.
et
al.
Calreticulin
mutations
and
longterm
survival
in
essential
thrombocythemia.
Leukemia
2014;28(12):2300–3.
DOI:
10.1038/leu.2014.148.
PMID:
24791854.Tefferi A., Wassie E.A., Lasho T.L. et al. Calreticulin mutations and longterm survival in essential thrombocythemia. Leukemia 2014;28(12):2300–3. DOI: 10.1038/leu.2014.148. PMID: 24791854.34.
 Andrikovics
H.,
Krahling
T.,
Balassa
K.

et
al.
Distinct
clinical
characteristics
of
myeloproliferative
neoplasms
with
calreticulin
mutations.
Haematologica
2014;99(7):1184–1190.
DOI:
10.3324/haematol.2014.107482.
PMID:
24895336.Andrikovics H., Krahling T., Balassa K. et al. Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations. Haematologica 2014;99(7):1184–1190. DOI: 10.3324/haematol.2014.107482. PMID: 24895336.35.
 Roques
M.,
Park
J.H.,
Minello
A.
et
al.

Detection
of
the
CALR
mutation
in
the
diagnosis
of
splanchnic
vein
thrombosis.

Br
J
Haematol
2015;169(4):601–603.

DOI:
10.1111/bjh.13235.
PMID:
25413838.Roques M., Park J.H., Minello A. et al. Detection of the CALR mutation in the diagnosis of splanchnic vein thrombosis. Br J Haematol 2015;169(4):601–603. DOI: 10.1111/bjh.13235. PMID: 25413838.36.
 Turon
F.,
Cervantes
F.,
Colomer
D.
et
al.
Role
of
calreticulin
mutations
in
the
aetiological
diagnosis
of
splanchnic
vein
thrombosis.
J
Hepatol
2015;62(1):72–74.

DOI:
10.1016/j.jhep.2014.08.032.

PMID:
25173966.Turon F., Cervantes F., Colomer D. et al. Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis. J Hepatol 2015;62(1):72–74. DOI: 10.1016/j.jhep.2014.08.032. PMID: 25173966.37.
 Sazawal
S.,
Singh
N.,
Mahapatra
M.
et
al.
Calreticulin
mutation
profile
in
Indian
patients
with
primary
myelofibrosis.
Hematology
2015;20(10):567–570.

DOI:
10.1179/1607845415Y.0000000018.
PMID:
25959795.Sazawal S., Singh N., Mahapatra M. et al. Calreticulin mutation profile in Indian patients with primary myelofibrosis. Hematology 2015;20(10):567–570. DOI: 10.1179/1607845415Y.0000000018. PMID: 25959795.38.
Tefferi
A.,
Lasho
T.L.,
Finke
C.
et
al.
Type
1
vs
type
2
calreticulin
mutations
in
primary
myelofibrosis:
differences
in
phenotype
and
prognostic
impact.
Leukemia
2014;28(7):1568–1570.
DOI:
10.1038/leu.2014.83.
PMID:
24569778.Tefferi A., Lasho T.L., Finke C. et al. Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia 2014;28(7):1568–1570. DOI: 10.1038/leu.2014.83. PMID: 24569778.39.
 Tefferi
A.,
Wassie
E.A.,
Guglielmelli
P.

et
al.
Type
1
versus
Type
2
calreticulin
mutations
in
essential
thrombocythemia:

a
collaborative
study
of
1027
patients.

Am
J
Hematol
2014;89(8):E121–E124.

DOI:
10.1002/ajh.23743.

PMID:
24753125.Tefferi A., Wassie E.A., Guglielmelli P. et al. Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol 2014;89(8):E121–E124. DOI: 10.1002/ajh.23743. PMID: 24753125.40.
 Tefferi
A.,
Vardiman
J.W.
Classification
and
diagnosis
of
myeloproliferative
neoplasms:
the
2008
World
Health
Organization
criteria
and
point-of-care
diagnostic
algorithms.
Leukemia
2008;22(1):14–22.

DOI:
10.1038/sj.leu.24049550.

PMID:
17882280.Tefferi A., Vardiman J.W. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22(1):14–22. DOI: 10.1038/sj.leu.24049550. PMID: 17882280.41.
 Cervantes
F.,
Dupriez
B.,
Pereira
A.
et
al.
New
prognostic
scoring
system
for
primary
myelofibrosis
based
on
a
study
of
the
International
Working
Group
for
Myelofibrosis

Research
and
Treatment. Blood 2009;113(13):2895–901.Cervantes F., Dupriez B., Pereira A. et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113(13):2895–901.42.
 Passamonti
F.,
Cervantes
F.,
Vannucchi
A.M.
et
al.
A
dynamic
prognostic
model
to
predict
survival
in
primary
myelofibrosis:a
study
by
the
IWG-MRT
(International
Working
Group
for
Myeloproliferative
Neoplasms
Research
and
Treatment).
Blood
2010;115(9):1703–8.Passamonti F., Cervantes F., Vannucchi A.M. et al. A dynamic prognostic model to predict survival in primary myelofibrosis:a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115(9):1703–8.43.
Al
Assaf
C.,
Van
Obbergh
F.,
Billiet
J.
et
al.
Analysis
of
phenotype
and
outcome

in
essential
thrombocythemia
with
CALR
or
JAK2
mutations.
Haematologica
2015;100(7):893–897.
DOI:
10.3324/haematol.2014.118299.
PMID:
25934766.Al Assaf C., Van Obbergh F., Billiet J. et al. Analysis of phenotype and outcome in essential thrombocythemia with CALR or JAK2 mutations. Haematologica 2015;100(7):893–897. DOI: 10.3324/haematol.2014.118299. PMID: 25934766.