2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

GENETICS OF MYELOPROLIFERATIVE NEOPLASMS
Fig. 1. Genetic and Epigenetic Dysregulation in Myeloproliferative Neoplasms. Adapted from Expert Review of Hematology, “JAK2 V617F
and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms,” Vol. 3, No. 3, June 2010, pages
323-327. Stephen Oh and Jason Gotlib, Figure 1, with permission of Expert Reviews Ltd.; and adapted with kind permission from Springer
Science and Business Media: Current Hematologic Malignancy Reports, “Disordered Epigenetic Regulation in the Pathophysiology of Myeloproliferative
Neoplasms,” vol. 7, no. 1, March 2012, pages 34-42, Su-Jiang Zhang and Omar Abdel-Wahab, Figure 1.
versely, transgenic models with more physiologic levels of
V617F expression resulted in phenotypes resembling ET
and PMF. 12 These animal models corroborate the findings
in patients in which V617F allele burden tends to be the
highest in PV and PMF, with lower levels in ET patients.
For ET patients, positivity for V617F tends to confer a
PV-like phenotype, with higher hemoglobin and lower platelet
counts than in V617F-negative ET patients. Differences
in intracellular signaling arising from V617F may also
explain the development of PV compared with ET: preferential
activation of STAT1 constrains erythroid differentiation
and promotes megakaryocytic development, leading to an
ET phenotype. 13 In contrast, reduced STAT1 phosphorylation
promotes erythroid development as observed in PV.
The type of hematopoietic progenitor(s) targeted by the
V617F mutation may contribute to differences in MPN
subtype. The V617F mutation is found in myeloid, or less
commonly, lymphoid lineage cells from MPN patients, suggesting
that it arises in a hematopoietic stem cell (HSC) or
early progenitor cell. 14 Jamieson and colleagues identified
the V617F mutation in cells from PV patients with an HSC
immunophenotype and demonstrated that these cells were
skewed toward the erythroid lineage. 15 These findings suggest
that either the V617F mutation induces erythroid
differentiation or that the mutation preferentially targets an
HSC subset already committed to an erythroid fate.
Host genetic background may also influence disease presentation.
In retroviral transplant models, disparate phenotypes
were observed depending on the mouse strain. In
C57Bl/6 mice, transplantation with JAK2 V617Ftransduced
cells resulted in a PV-like disease predominantly
characterized by erythrocytosis. 16 However, in Balb/C mice,
similar experiments yielded mice with erythrocytosis, but
also leukocytosis and the subsequent development of myelofibrosis.
17
Perhaps the most compelling basis for MPN diversity
comes from the additional molecular abnormalities that
either precede or follow the acquisition of V617F (Table 2).
The aggregate data suggest that there is no strict temporal
order of mutation occurrence that defines the development
or natural history of specific MPNs. However, several lines
of evidence support that V617F may arise on a pre-existing
abnormal clonal substrate: 1) in some patients, the V617F
burden is relatively small compared with the proportion of
cells with a coexistent clonal karyotypic abnormality; and
2) in AML arising from a V617F-positive MPN, the mutant
V617F allele can frequently no longer be detected. 18 This
suggests that the MPN and AML share a clonal origin that
likely preceded the acquisition of V617F. Furthermore, in
V617F-positive PV and ET patients, both JAK2 wild-type
and V617F-positive EECs have been detected within the
same patient, suggesting that a separate event may confer
clonal, erythropoietin-independent growth, before V617F.
One study in ET patients demonstrated that V617F was
acquired on separate alleles as multiple, independent
events. 19 Therefore, at least for ET, the V617F mutation
does not necessarily confer clonal dominance, permitting
JAK2 V617F-negative cells to continue to proliferate and
subsequently acquire the V617F mutation independently.
Activated JAK-STAT Signaling without JAK2 V617F
In the absence of V617F, activation of JAK-STAT signaling
can be demonstrated in some MPN patients, suggesting
that molecular alterations that interdigitate with this axis
may contribute to MPN pathogenesis. This paradigm is
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