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Haematological Malignancies

Leukaemic Transformation of Philadelphia-chromosome-negative Myeloproliferative Neoplasms – A Review of the Molecular Background

Nils H Thoennissen1 and H Phillip Koeffler2

1. Post-doctoral Researcher, Division of Hematology/Oncology, Cedars-Sinai Medical Center; 2. Director, Division of Hematology/Oncology, Cedars-Sinai Medical Center, and Deputy Director of Cancer Research, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore


Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET), are clonal haematopoietic stem cell disorders characterised by proliferation of one or more myeloid cell lineages. They are closely associated with the JAK2V617F mutation, whose detection is used as a clonal marker in the differential diagnosis of MPN. Despite recent improvements in the molecular diagnosis and therapeutic regimen of these chronic disorders, haematological evolution to blast phase remains a major cause of long-term mortality. The mechanism of MPN transformation is still a matter of some controversy because of insufficient insights into the underlying molecular pathogenesis. The purpose of this article is to summarise the increasing data concerning the mechanism of leukaemic evolution of patients diagnosed with chronic MPN. Chromosomal abnormalities and genes that have been shown to play a potential causative role in chronic-phase acceleration are discussed, as are aberrations that may serve as prognostic markers in the blast phase of MPN.

Keywords Philadelphia-chromosome-negative myeloproliferative neoplasms, leukaemic transformation

Disclosure: The authors have no conflicts of interest to declare. Received: 15 March 2010 Accepted: 3 July 2010 Citation: European Oncology & Haematology, 2011;7(1):59–62 Correspondence: Nils H Thoennissen, Division of Hematology and Oncology, Cedars Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Blvd, Los Angeles, CA 90048, US. E:

Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET) are defined as clonal haematopoietic stem cell disorders. They are characterised by increased proliferation of terminally differentiated myeloid cells.

In recent years, much progress has been made in understanding the molecular origin of these chronic entities. The tyrosine kinase JAK2 and thrombopoietin receptor (MPL) were directly linked to the pathogenesis of MPN with the identification of somatic mutations including JAK2V617F, or rare variants, as well as MPL515.1,2


different mutant alleles all result in a gain of function due to the constitutive activation of tyrosine kinase-dependent cellular signalling pathways.2–4

Recently discovered deletions or mutations involving

TET2, ASXL1 and IDH1/2 shed more light on possible mechanisms of excessive proliferation in chronic MPN.5–7

Among the classic MPNs, PV

and ET are relatively indolent disorders, resulting in a modest reduction of lifespan compared with a control population; however, most patients ultimately suffer from one or more severe and potentially fatal complications directly attributable to the disease. By comparison, in most cases PMF has a more severe course and survival is significantly affected.8–12

Nonetheless, MPN patients are at a significantly increased risk of transformation to acute myelogenous leukaemia (AML), which is generally associated with a dismal prognosis. The incidence of


chronic-phase MPN is two to five cases per 100,000 population per year,12

whereas leukaemic evolution occurs in 2–5% of these patients with either PV or ET8,9

and roughly 20% of cases with PMF.10,11

Patients with de novo and secondary AML have a similar spectrum of structural abnormalities, including specific chromosomal sites. The occurrence of cytogenetic changes associated with unfavourable risk such as -7/7q- or complex karyotype is higher in secondary AML. These changes are most probably induced by the type of therapy given during the chronic phase of MPN.11,13–15

Apart from the chromosomal

alterations, cumulative insights have been made into the causative genes that underlie the leukaemic transformation of chronic MPNs.

Recent findings have suggested that transition from heterozygosity to homozygosity for JAK2V617F is associated with an increased hyperproliferative disease and may be important for disease progression, at least from PV to secondary myelofibrosis.16


one longitudinal prospective study suggested that the presence of a JAK2V617F haematopoietic clone was significantly associated with leukaemic transformation in PMF.17

The role of JAK2V617F in clonal

evolution is of particular interest as the examination of its kinetics could potentially allow the prediction of disease acceleration. It could also determine whether treatment with novel JAK2 inhibitors during the chronic phase of MPN may be effective in reducing the incidence of transformation. However, our group at the Cedars-Sinai Medical Center showed no statistical difference between the time to transformation in MPD patients with homozygous JAK2V617F


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