Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.
BACKGROUND
An acquired V617F mutation in JAK2 occurs in most patients with polycythaemia vera, but is seen in only half those with essential thrombocythaemia and idiopathic myelofibrosis. We aimed to assess whether patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes.


METHODS
Two sensitive PCR-based methods were used to assess the JAK2 mutation status of 806 patients with essential thrombocythaemia, including 776 from the Medical Research Council's Primary Thrombocythaemia trial (MRC PT-1) and two other prospective studies. Laboratory and clinical features, response to treatment, and clinical events were compared for V617F-positive and V617F-negative patients with essential thrombocythaemia.


RESULTS
Mutation-positive patients had multiple features resembling polycythaemia vera, with significantly increased haemoglobin (mean increase 9.6 g/L, 95% CI 7.6-11.6 g/L; p<0.0001), neutrophil counts (1.1x10(9)/L, 0.7-1.5x10(9)/L; p<0.0001), bone marrow erythropoiesis and granulopoiesis, more venous thromboses, and a higher rate of polycythaemic transformation than those without the mutation. Mutation-positive patients had lower serum erythropoietin (mean decrease 13.8 U/L; 95% CI, 10.8-16.9 U/L; p<0.0001) and ferritin (n=182; median 58 vs 91 mug/L; p=0.01) concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features that were characteristic of a myeloproliferative disorder. V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation.


CONCLUSIONS
Our results suggest that JAK2 V617F-positive essential thrombocythaemia and polycythaemia vera form a biological continuum, with the degree of erythrocytosis determined by physiological or genetic modifiers.
Campbell
Peter J
PJ
Department of Haematology, University of Cambridge, UK.
Scott
Linda M
LM
Buck
Georgina
G
Wheatley
Keith
K
East
Clare L
CL
Marsden
Joanne T
JT
Duffy
Audrey
A
Boyd
Elaine M
EM
Bench
Anthony J
AJ
Scott
Mike A
MA
Vassiliou
George S
GS
Milligan
Donald W
DW
Smith
Steve R
SR
Erber
Wendy N
WN
Bareford
David
D
Wilkins
Bridget S
BS
Reilly
John T
JT
Harrison
Claire N
CN
Green
Anthony R
AR
D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011087:Polycythemia Vera / Q000235:genetics*; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013921:Thrombocytopenia / Q000145:classification / Q000235:genetics*
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2