Myeloid Leukemia

254 Campbell et al.
is not too dissimilar to age- and sex-matched reference populations (6,7). IMF,
on the other hand, is dominated by marrow fibrosis, together with signs of
extramedullary hematopoiesis, with ensuing bone marrow failure as the condition
progresses (8). All three MPDs can transform to acute myeloid leukemia,
albeit at low rates, and PV and ET can undergo secondary myelofibrotic transformation.
Diagnostic criteria have been controversial (8–10), often relying on
excluding other diagnoses that can present with elevated blood counts, and on
markers, such as erythropoietin levels and erythropoietin-independent erythroid
colony (EEC) growth, tests that are not universally available.
Recently, our understanding of the molecular mechanisms underlying MPDs
has been advanced by the description of a mutation in the JAK2 gene (11–14),
a key hematopoietic regulator. When sensitive methods are used for the detection
of the V617F mutation, it is found in virtually all cases of PV, and about
one-half of cases of ET and IMF (11). The JAK family members (JAK1, JAK2,
TYK2, JAK3) act as non-receptor tyrosine kinases, being activated in response
to cytokines that utilize cytokine receptor super-family members. Considerable
evidence has suggested that ligand binding leads to oligomerization of the
receptor chains and their associated JAK proteins, resulting in JAK transphosphorylation
and catalytic activation. The JAKs in turn tyrosine-phosphorylate
the cytokine receptors, as well as a variety of cellular substrates that are
recruited to the activated receptor complexes. The V617F mutation promotes
constitutive autophosphorylation of the JAK2 protein, with subsequent activation
of downstream effectors (12,13), and leads to erythrocytosis in a murine
retrovirus model (12).
Because the V617F mutation is a single mutation that occurs very frequently
in MPDs (and not in normal individuals), its reliable detection in a routine
laboratory setting will facilitate the diagnostic assessment of patients being
evaluated for a possible MPD. Presence of the V617F mutation indicates that
the patient has an acquired, clonal hematological disorder and not a reactive or
secondary process. Absence of the JAK2 V617F mutation does not exclude a
MPD, because up to 50% of patients with ET and IMF do not have this mutation.
The V617F mutation does not help in sub-classifying the type of MPD of
a given patient, and thus does not supplant the need for a bone marrow or red
cell mass evaluation. The low frequency of the mutation in other disorders,
such as acute myeloid leukemia (15), myelodysplasia (15,16), and other cancers
(15), also indicates a degree of specificity for PV, ET, and IMF.
MPDs are stem cell disorders in which a proportion of circulating granulocytes
are clonally derived. Therefore, they are amenable to mutation analysis
on peripheral blood. However, the proportion of clonal granulocytes is variable
(17,18). Thus, a molecular test for the V617F mutation must be suffi-