Myeloproliferative Disorders. HongzhiXu Shandong Provincial Hospital. CONTENTS. Pathogenesis and management of essential thrombocythemia Idiopathic erythrocytosis: a disappearing entity Therapeutic potential of JAK2 inhibitors.
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The level of JAK2-STAT5 signaling provides a rheostat that determines whether the disease phenotype is predominantly erythroid or megakaryocytic.
Several lines of evidence suggest a blurring of the distinction between these disorders. A proporation of patients diagnosed with ET (see Table 1 for criteria) harbor increased levels of bone marrow reticulin in the absence of other features suggesting a diagnosis of PMF
The variable degree of reticulin accumulation reflects the combined effects of genetic background, disease duration, therapy, clonal burden and the acquisition of additional genetic lesions.
Diagnosis requires A1-A3 OR A1+A3-A5
A relative risk of 7.4 for developing ET in those with an affected first-degree relative.
The acquisition of a JAK2 mutation was preceded by either a deletion of chromosome 20q24 or a mutation in TET2.
Direct evidence now exists demonstrating that JAK2 mutations are not the disease-initiating event in some patients, although the frequency of this scenario remains unclear.
Progression to Acute Myeloid Leukemia Neoplasms
Progression to acute myeloid leukemia(AML) occurs in a small minority of ET patients and involves the accrual of further genetic events.
Mutations in JAK2 exon 12 are not thought to occur in patients with ET.
The combination of an isolated thrombocytosis with a pathogenetic mutation, in the absence of iron deficiency or features of PMF, is usually sufficient to make a diagnosis of ET.
An erythrocytosis can be classified depending on the identified cause. The main division is on the basis of primary causes, where an intrinsic defect in the erythroid progenitor cell is associated with an enhanced response to cytokines; or secondary, where the increased red cell production is driven by factors external to the erythroid compartment, such as increased erythropoietin(EPO) production for any reason. Primary and secondary causes can be classified further as either congenital or acquired(Table2).
Erythropoietin(EPO) receptor mutations
Polycythemia vera (including JAK2 exon 12 mutations)
Defects of the oxygen sensing pathway
VHL gene mutation (Chuvash erythrocytosis)
Other congenital defects
High oxygen-affinity hemoglobin
Bisphosphoglycerate mutase deficiency
Chronic lung disease
Right-to-left cardiopulmonary vascular shunts
Carbon monoxide poisoning
Hypoventilation syndromes including obstru-
ctive sleep apnea
Local hypoxia Neoplasms
Renal artery stenosis
End-stage renal disease
Renal cysts (polycystic kidney disease)
Post-renal transplant erythrocytosis
Pathologic EPO production Neoplasms
Renal cell cancer
Once an erythrocytosis has been established identification of the cause is the next focus.
A raised red cell count will increase the viscosity and thus may have clinical consequences.
Reducing the Hct by phlebotomy/venesection reduces the blood viscosity and maybe of benefit.
The V617F mutation is localized in a region outside the adenosine triphosphate(ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme.
While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones.
Most importantly, patients with and without the JAK2 V617F mutation appear to benefit to the same extent.
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