The molecular pathogenesis of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological stem cell
malignancies characterised by proliferation of one or more cells of the myeloid lineage. The molecular
investigation of MPN was revolutionized in 2005 by the finding that approximately 95% of cases with
polycythaemia vera (PV) and 50-60% of cases of essential thrombocythaemia (ET) and primary
myelofibrosis (PMF) are characterised by a single acquired mutation, JAK2 V617F. My study has
focused on four principal areas:

(i) Involvement of V617F in other myeloid disorders. After developing sensitive methods to
detect and quantify V617F, this mutation was identified in 17% of cases of atypical chronic myeloid
leukaemia (17/99) as well as other atypical MPN, thus demonstrating that it was more widely
involved in myeloid disorders that initially thought. Homozygosity of V617F was shown to have arisen
by acquired uniparental disomy (UPD) and examination of two cases with V617F plus either KIT
D816V or BCR-ABL demonstrated that the mutations had arisen in independent clones.

(ii) In vitro assays to predict imatinib sensitivity. Haemopoietic colony and liquid cultures were
used to determine if peripheral blood or bone marrow cells from atypical MPN cases (n=200) were
sensitive to imatinib. Of those that responded in one or both cultures (n=185) some had known
abnormalities of PDGFRA or PDGFRB, but a significant minority proved negative for all molecular tests
suggesting the presence of uncharacterised imatinib-sensitive mutations.

(iii) V617F as a marker of response to therapy. JAK2 V617F was used as a molecular marker to
monitor the response of PV patients (n=21) to therapy with imatinib and interferon-?. Neither
therapy eradicated V617F but there was a modest reduction in %V617F which correlated with
haematological response. By contrast, in those patients that did not respond (n=13) the %V617F
marginally increased.

(iv) Genetic predisposition to MPN. Whilst investigating the possible contribution of JAK2 single
nucleotide polymorphisms to the phenotypic diversity associated with V617F, marked skewing of
alleles associated with the mutation was observed. Further investigation revealed that V617Fassociated
disease is strongly associated with a specific constitutional JAK2 haplotype, designated
46/1, in all three disease entities compared to healthy controls (PV, n=192, P=2.9x10-16; ET, n=78,
P=8.2x10-9 and MF, n=41, P=8.0x10-5). Furthermore, allele-specific PCR demonstrated that V617F
specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the
development of V617F associated MPNs (OR=3.7; 95% CI 3.1-4.3) and provides a model whereby a
constitutional genetic factor is associated with an increased risk of acquiring a specific somatic
mutation.

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Identifiers

ORCID for Nicholas Cross: orcid.org/0000-0001-5481-2555

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