Page 1239 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 68 The Polycythemias 1085

increasing evidence shows that PV is not solely initiated by MPL mutations. How this JAK2 SNP promotes the development of
JAK2V617F. The fact that JAK2V617F has been identified in patients JAK2V617F MPNs remains the subject of great speculation, but two
with three phenotypically related but clinically distinct MPNs sug- hypotheses have been proposed: (1) hypermutability of the chromo-
gests that additional genetic or epigenetic events likely contribute to some region facilitates the acquisition of somatic mutation; or (2) the
the phenotypic divergence of these disorders. These differing disease JAK2 SNP confers a selective proliferative advantage, the so-called
phenotypes have been hypothesized to be caused by striking differ- fertile ground hypothesis. Recently, germ-line polymorphisms in the
ences in the degree to which the mutation activates the JAK-STAT TERT gene have also been reported to predispose to JAK2V617F-
pathway. Mutant JAK2 activates multiple cytokine receptor-associated positive and -negative sporadic and familial MPNs. The predisposi-
pathways, including STAT1 and STAT5, which can have competing tion was far stronger in familial than sporadic MPNs, suggesting that
consequences. STAT1 appears to be activated in association with low-penetrance variants might be responsible for the familial cluster-
JAK2V617F ET but not PV. Inhibition of STAT1 in ET progenitor ing of MPNs. Two additional SNPs involving TERT and HBS1L/
cells enhances erythropoiesis, indicating that in ET, the phospo- MYB were shown to have a stronger association with MPN popula-
15
STAT1 response to JAK2V617F constrains erythropoiesis and pro- tions with CALR or MPL mutations that lacked JAK2V617F.
motes megakaryocytic differentiation, but in PV, the reduced pSTAT1 Reduced expression of MYB has been linked to ET-like disease in
response removes the break on erythropoiesis, allowing enhanced several animal models. In JAK2V617FJAK2V617F-positive individu-
erythropoiesis to occur. als, the reduced MYB associated with the MYB SNP favored the
The role of JAK2V617F in the underlying pathogenesis of PV has development of an ET phenotype. In addition, polymorphisms of
been extensively explored using either restricted fragment length the glucocorticoid receptor have been associated with PV and PMF
polymorphism analysis or the presence of marker cytogenetic abnor- but not ET.
malities in patients with MPNs. The percentage of granulocytes and In the MPNs, acquisition of mutations in either TET2 or JAK2
platelets that are JAK2V617F positive is often lower than the percent- may occur first, but those patients that acquire JAK2V617F first are
age of granulocytes belonging to the malignant clone. In addition, more likely to develop PV. The concept that the MPN phenotype is
these marker cytogenetic abnormalities may occur before or after the the consequence of the order of mutational acquisition was first
16
acquisition of JAK2V617F. Furthermore JAK2V617F-negative ery- proposed by Ortmann and coworkers. JAK2 and TET2 mutations
throid colonies have been cloned in vitro in the absence of the each occurred first in 50% of patients. JAK2V617F homozygosity
addition of EPO, a hallmark of PV, indicating the presence of an was not required for acquisition of a TET2 mutation to occur. JAK2
undefined molecular lesion that precedes the JAK2V617 mutation. first patients were more likely to present with PV, were younger, more
Several investigators have reported families in which multiple sensitive to ruxolitinib treatment, and were more likely to suffer from
members have MPNs, including PV, ET, PMF, and CML, and have a thrombotic event than those individuals who acquired a TET2
analyzed the JAK2V617F and CALR status of family members. The mutation initially. These data indicate that the order of acquisition
families with multiple members with MPNs have been analyzed for of mutations might influence the clinical phenotype of the resultant
mutational status. In affected patients the JAK2V617F mutation was MPN. TET2 mutations have been shown to result in expansion of
the most commonly acquired followed by CALR exon 9 mutations, the malignant clone in elderly persons with normal blood counts,
with no MPL W515L/K mutations being detected. Interestingly, in and in murine studies, a double-mutant TET2–JAK2 clone was out
some families, both JAK2V617F-positive and -negative members competed by its TET2 single-mutant ancestor. In mice, expression of
with MPN were observed. A small number of relatives who were JAK2 V617F but not TET2 resulted in increased erythropoiesis. A
JAK2V617F negative and did not have a diagnosis of PV, ET, or PMF TET2-inactivating mutation but not JAK2V617F leads to hemato-
had hematopoietic cells that formed endogenous erythroid colonies poietic stem cell expansion. The report by Ortmann and coworkers
in vitro. Disease evolution can be highly variable within families suggests that in patients who acquire TET2 first, TET2 single-mutant
presenting with the same type of MPN. These results suggest that an hematopoietic stem and progenitor cells expand but do not give rise
as yet unidentified genetic event, either germ-line or somatic, might to excess differentiated megakaryocytic and erythroid cells until a
contribute to the pathogenesis of PV, ET, and PMF, regardless of JAK2 mutation is acquired. By contrast, in patients who acquire
JAK2 mutational status, and that there may be “initiating events” that JAK2 first, JAK2 single-mutant hematopoietic stem and progenitor
precede the acquisition of JAK2V617F in these disorders. Acquired cells generate increased numbers of megakaryocytic and erythroid
mutations of the ten–eleven translocation 2 gene (TET2), which are cells, and stem cell numbers only expand after acquisition of a TET2
discussed in greater detail in Chapter 70, were studied in these fami- mutation. This model is consistent with the earlier clinical presenta-
lies to determine if it was a gene that played a role in PV before tion of patients who first acquire a JAK2 mutation since they more
acquisition of JAK2V617F. These acquired TET2 mutations occurred rapidly generate excess megakaryocytic and erythroid cells. The initial
in approximately 12% of patients with sporadic MPNs. The fre- TET2 mutation may modify the epigenetic program of HSCs and
quency and types of TET2 mutations in patients with familial MPNs progenitor cells, and thus alter the consequences of the second muta-
were similar to that observed in sporadic MPNs. As a whole, 20% of tion. A prior mutation of TET2 alters the transcriptional consequences
the family members with JAK2V617F MPNs have TET2 mutations, of JAK2 V617F in a cell-intrinsic manner and prevents JAK2 V617F
and 17% of JAK2V617F-negative members had a MPN with a TET2 from upregulating stem and progenitor cell proliferation.
mutation. In addition, the TET2 mutation may occur either before
or after the acquisition of JAK2V617F. When JAK2V617F coexisted
with TET2, the TET2 allele burden varied from 20% to 60%. Dif- The JAK2V617F Mutation Is Present in Hematopoietic
ferent TET2 mutations were observed in affected members of the Stem Cells in Polycythemia Vera
same family and were shown to be acquired, indicating that TET2
mutations were not a major predisposing factor to either sporadic or Previous studies had demonstrated that the majority of patients with
familial MPNS. Familial clustering of MPNs supports the evidence PV had clonal involvement of multiple lineages, including myeloid,
that the pathologic phenotype is driven by yet to be defined suscep- erythroid, and lymphoid cells. These results suggested that PV origi-
tibility genes. nates in hematopoietic progenitors with the ability to differentiate
Evidence has accumulated from epidemiological and familial into multiple lineages. In addition, LOH at 9p24, known to corre-
studies that indicate that common low-penetrance factors present in spond to homozygous JAK2V617F mutations, can be identified in
the general population contribute to the risk of developing an MPN both myeloid and lymphoid cells in some patients with PV, further
and possibly to the phenotype of the particular MPN. The germ-line suggesting that the underlying mutations occur in progenitor cells
constitutive JAK2 haplotype, called GGCC or 46/1, has been shown with the ability to differentiate into multiple hematopoietic
to be a susceptibility factor for the development of JAK2V617F- lineages.
14
positive PV. The JAK2 46/1 haplotype is also weakly associated with The JAK2V617F mutation has been detected in hematopoietic
exon 12 JAK2 PV, MPL W515 MPNs, as well as MPNs that lack colony-forming cells and more mature progeny, such as neutrophils