Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.
Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.
Levine
Ross L
RL
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wadleigh
Martha
M
Cools
Jan
J
Ebert
Benjamin L
BL
Wernig
Gerlinde
G
Huntly
Brian J P
BJ
Boggon
Titus J
TJ
Wlodarska
Iwona
I
Clark
Jennifer J
JJ
Moore
Sandra
S
Adelsperger
Jennifer
J
Koo
Sumin
S
Lee
Jeffrey C
JC
Gabriel
Stacey
S
Mercher
Thomas
T
D'Andrea
Alan
A
Fröhling
Stefan
S
Döhner
Konstanze
K
Marynen
Peter
P
Vandenberghe
Peter
P
Mesa
Ruben A
RA
Tefferi
Ayalew
A
Griffin
James D
JD
Eck
Michael J
MJ
Sellers
William R
WR
Meyerson
Matthew
M
Golub
Todd R
TR
Lee
Stephanie J
SJ
Gilliland
D Gary
DG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005838:Genotype; D006098:Granulocytes / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics; D008958:Models, Molecular; D009061:Mouth Mucosa / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000150:complications / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000235:genetics*; D014162:Transfection
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2