Hellman_edit.qxp 12/8/09 5:30 pm Page 57
Haematological Malignancies
Myeloproliferative Neoplasms – Classification, Diagnostic and
Therapeutic Options in the Light of Molecular Findings
Andrzej Hellmann
1
and Maria Bieniaszewska
2
1. Professor of Medicine, and Head; 2. Haematologist, Department of Haematology and Transplantology, Medical University of Gdansk
Abstract
The discovery of specific molecular aberrations (gene fusions or mutations) has had a profound effect on the understanding and
management of myeloproliferative disorders (MPDs). First, it has provided clear evidence that all of these disorders are of neoplastic origin.
This fact resulted in the change of the nomenclature proposed in the World Health Organization (WHO) Classification of Tumours of
Haematopoietic and Lymphoid Tissues 2008, where the term MPDs was replaced by myeloproliferative neoplasms (MPNs). Second, useful
tools for diagnostic procedures were developed, i.e. polymerase chain reaction (PCR) or other molecular assays. Thanks to this, previous
complicated diagnostic algorithms could be simplified and the numerical value requirements could be lowered, making the diagnosis
simpler and quicker. The other implication of the molecular findings in myeloproliferative neoplasms is derived from the fact that all
discovered mutations result in translation of proteins with tyrosine kinase activity. So, nowadays the majority of myeloproliferative
neoplasms can be treated with target therapy using tyrosine kinase inhibitors.
Keywords
Myeloproliferative neoplasms, gene mutations, classification, diagnostic criteria, target therapy, tyrosine kinase inhibitors
Disclosure: The authors have no conflicts of interest to declare.
Received: 22 May 2009 Accepted: 3 July 2009
Correspondence: Andrzej Hellmann, Department of Haematology and Transplantology, Medical University of Gdansk, Debinki 7, 80-952 Gdansk, Poland.
E:
klhem@gumed.edu.pl
The term myeloproliferative disorders (MPDs) was introduced by These factors were manifested in the 2001 edition of the World Health
Demeshek in 1951.
1
He postulated that various clinical conditions, Organization (WHO) Classification of Tumours of Haematopoietic and
such as chronic granulocytic leukaemia, polycythaemia vera (PV), Lymphoid Tissues, in which all of the disorders mentioned above were
idiopathic myeloid metaplasia, thrombocythaemia, megacariocytic included in a chapter entitled ‘Myeloproliferative Diseases’.
6
At that time
leukaemia and erythroleukaemia, can be regarded as variable the term neoplasm was not used because there was a lack of solid
manifestations of proliferative activity of bone marrow cells. In the criteria that in every case permitted the distinction of reactive from
following few years, the term MPD was limited to forms of disease in neoplastic proliferation. This is best illustrated by the fact that in the case
which maturation of cells is preserved and – in contrast to acute of chronic eosinophilic leukaemia (CEL) the term hypereosinophilic
leukaemias – the natural course is usually characterised by benign syndrome was preserved. Mastocytosis was presented in this
onset. Finally, four diseases – chronic myelogenous leukaemia (CML), classification as a different entity, where cutaneous, usually benign,
PV, essential thrombocythaemia (ET) and myelofibrosis (MF) – were mastocytosis was put together with systemic forms of the disease.
recognised as classic MPDs. In 1968, Hardy and Anderson introduced
the term ‘hypereosinophilic syndrome’ (HES),
2
for which Chusid et al. The development and achievements of molecular biology in the last 25
proposed more defined criteria.
3
HES was regarded by some authors years have confirmed the concept of the neoplastic nature of these
as a fifth form of MPD. diseases. In almost all of the mentioned disorders, specific molecular
markers were found in the form of either gene mutations or gene fusions.
Originally, Demeshek assumed that these disorders and their different In 1984, the BCR/ABL fusion gene, the result of a translocation between
clinical manifestations resulted from the action of undiscovered the 9 and 22 chromosomes, in 1993, the KIT gene mutation characteristic
myelostimulatory factors or mechanisms. Twenty-seven years later, of systemic mastocytosis and in 2003, the FLIP1L1/ PDGFRA fusion gene
Adamson and Fialkow postulated that the carcinogenic mutation of characteristic for CEL were described.
7,8,9
Two years later, the JAK2 gene
multipotential stem cells is the underlying cause of MPD.
4
The discovery mutation, found in the majority of PV cases and at least half of ET and MF
of the Philadelphia chromosome (Ph) as a constant cytogenetic cases, was uncovered.
10–12
All of the mentioned mutations result in
aberration in CML, the 6-phospho gluconate dehydrogenase (6-GPD) translation of proteins with tyrosine kinase activity. They are responsible
isoenzyme studies in heterozygous females with PV and ET started by for constitutive activations of molecular pathways, leading to
Fialkow in 1974 and the clonogenic assay introduced by Bradley and uncontrolled cell proliferation in MPDs. So, although these mutations
Metcalf confirmed the hypothesis of the clonal nature of MPDs also in have proved the neoplastic origin of MPDs, in some ways they are in
cases of hypereosinophilic syndrome.
5
accordance with Dameshek’s concept of dysregulation of myelopoesis.
© TOUCH BRIEFINGS 2009 57
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68