JAK Signaling Hypothesis
Targeting the JAK* pathway: a novel investigational approach to myelofibrosis and
other myeloproliferative neoplasms
Myelofibrosis (MF) belongs to a group of malignancies known as myeloproliferative
neoplasms (MPNs), previously referred to as myeloproliferative disorders (MPDs),
which also include polycythemia vera and essential thrombocythemia.1
They are characterized by the abnormal proliferation of myeloid-lineage
blood cells.2 Clinical manifestations of MF include splenomegaly,
bone marrow fibrosis, and extramedullary hematopoiesis.3 Among patients
with primary MF, about 12% develop life-threatening leukemic
transformation.4 Quality of life in patients with MF is affected
by severe symptoms, including fatigue (85%), pruritus (39%), bone pain (51%),
and weight loss (30%).5
JAK signaling, a pathway that mediates cytokine signal transduction,
is intimately involved in the pathogenesis of Philadelphia
chromosome-negative MPNs.6 A point mutation in JAK2,
JAK2V617F, is present in about 50% to 60% of patients with
primary MF and essential thrombocythemia and in over 95% of cases of
polycythemia vera.2 This mutation results in constitutive
activation of the JAK pathway.2 Although JAK2 mutational
status is helpful in MPN diagnosis, it is not a predictive marker of
response to JAK inhibitor treatment.7 This may be due in part
to other mechanisms of hyperactivation of JAK signaling, such as excess
cytokines or other receptor or kinase mutations.2 Therefore,
inhibition of the JAK pathway represents a novel approach in the treatment
of MPNs.7
