ABSTRACT
Exaggerated erythropoiesis and megakaryocytopoiesis are present at a variable extent
in polycythemia vera (PV) and essential thrombocythemia (ET). With the recent discovery
of the V617F mutation in the Janus kinase 2 (JAK2) tyrosine kinase in almost all cases
of PV and in a subset of patients with ET, studies are now pending to assess the role
of this mutation in the hematopoietic cell activation process and/or in the occurrence
of thromboses in ET and PV. The JAK2 V617F point mutation makes the normal hematopoietic
progenitor cells hypersensitive to thrombopoietin, erythropoietin, and myeloid progenitor
cells, leading to trilinear hematopoietic myeloproliferation. This will have three
main clinical consequences during long-term follow-up. First, spontaneous growth of
enlarged mature megakaryocytes in ET/PV with overproduction of hypersensitive platelets
results in a broad spectrum of platelet-mediated microvascular circulatory disturbances,
which are very sensitive to low-dose aspirin. Second, spontaneous growth of erythropoiesis
with the overproduction of erythrocytes leads to classic PV with increased hemoglobin,
hematocrit, and red cell mass. This is associated with a high frequency of major arterial
and venous thrombotic complications in addition to platelet-mediated microvascular
circulatory disturbances of thrombocythemia. Third, the slowly progressive myeloid
(granulocytic) metaplasia in bone marrow and spleen is complicated by secondary myelofibrosis
caused by a megakaryocytic/granulocytic cytokine storm in about one fourth to one
third of JAK2 V617F-positive PV patients after long-term follow-up, with no tendency
of leukemic transformation as long as they are not treated with myelosuppressive agents.
Randomized clinical trials directly comparing phlebotomy versus hydroxyurea or interferon
α versus hydroxyurea in PV with progressive disease are lacking. Heterozygous V617F
mutation is enough to produce the clinical picture of ET with a slight tendency to
increased hemoglobin and hematocrit (early PV mimicking ET). Homozygous V617F mutation
is associated with the clinical picture of classic PV and with a higher tendency to
secondary myelofibrosis, but with no increased leukemia unless other biological or
genetic factors come into play, such as myelosuppressive agents or the acquisition
of additional biologic or genetic defects. Depending on the biological background
of individual patients, heterozygous and homozygous JAK2 V617F ET/PV may preferentially
induce myeloid metaplasia with myelofibrosis with a relative suppression of megakaryocytic
and erythropoietic myeloproliferation leading to clinical pictures of fibrotic chronic
idiopathic myelofibrosis (CIMF) or agnogenic myeloid metaplasia. The main conclusion
is that JAK2 V617F is a 100% specific clue to a new distinct clonal myeloproliferative
disorder. JAK2 V617F-positive ET/PV and CIMF should be distinguished from wild-type
JAK2 ET, rare cases of PV, and CIMF, and should be evaluated during life-long follow-up.
KEYWORDS
Essential thrombocythemia - polycythemia vera - myeloproliferative disorders - platelet
activation - thrombosis - leukocyte/platelet activation
REFERENCES
Treatment of polycythemia vera: a summary of clinical trials conducted by the Polycythemia
Vera study Group . In.: Wasserman LR, Berk PD, Berlin NI Polycythemia Vera and the Myeloproliferative
Disorders. Philadelphia, PA; WB Saunders 1995
sylvia.bellucci@lrb.ap-hop-paris.fr
