4. Hrvatski kongres kliniËke citologije 4th Croatian Congress ... - Penta

Analytical Cytology - Plenary and Invited Lectures
MOLECULAR PATHOGENESIS OF PHILADELPHIA-NEGATIVE CHRONIC MYLEOID
NEOPLASMS
Kušec R
Department of Hematology and Molecular diagnostics and genetics, Dubrava University
Hospital, and Zagreb School of Medicine, Zagreb, Croatia
Myeloproliferative disorders or neoplasms (MPNs), as they have recently been renamed
by the WHO 2008 classification, have been divided into polycythaemia vera (PV), essential
thrombocythaemia (ET) and primary myelofibrosis (PMF). The discovery of the JAK2
V617F mutation in nearly all patients with PV and half those with ET and PMF has redefined
the classification and will most likely influence the management of MPNs in the
near future. It seems likely, however, that any attempt to reclassify the MPNs on the
basis of JAK2 mutation status will need to retain the concepts of a disease with predominant
erythrocytosis, a disease with predominant marrow fibrosis and a disease with
isolated thrombocytosis, since both therapy and prognosis vary substantially across the
three entities. Examination of the JAK/STAT signaling pathway and cytokine receptors
led to the discovery of various gain-of-function mutations in the thrombopoietin receptor
(MPL). They occur in patients with PMF and ET with a frequency of 1-9%. Both JAK2
and MPL mutations, as shown in animal models, clearly induce a myeloproliferative
phenotype in vivo. For JAK2 it was shown that ratio of mutant JAK2-V617F to wild-type
JAK2 determines the MPD phenotype in transgenic mice. Monoclonal origin of MPNs
has been a pathogenetic fundamental and extensive studies at cytogenetic and molecular
level are being conducted in search of invariant aberration of MPN specific (gene)
defect. This has not been found so far. In cytogenetics lesions frequently seen in other
myeloid neoplasms were detected: deletions (chr5q,13q,20q), numerical changes (1,8,9)
and gains of 9p. For the increase in mutated allele frequency of JAK2 V617F a mechanism
of uniparental disomy (UPD) of the short arm of chromsome 9 (9UPD) was found
to be the most frequent mechanism. Besides JAK2 and MPL, recently other sporadic
oncogenic point or other type of mutations (mostly small deletions) have been found in
different oncogenes (e.g. TET2, CBL, IKZF1). However, all of them in a relatively small
proportion and different MPN phenotypic subtypes. All these lesions create number of
genotype classes of progenitors and when cultured progenitor colonies are genotyped
complex pattern of different clones is found in which also variable acquisition order
of genetic abberations is evident. Simulatanously occuring two different mutations are
possible (JAK2 and MPL, or two independent JAK2 mutations) which suggests that MPN
exhibits a certain form of mutator phenotype resulting in increased mutation frequency.
Recently an MPN susceptibility haplotype of JAK2 was identified based on the uneven
distribution of JAK2 V617F mutations between the two most frequent haplotypes. While
it still remains to be seen wheter and which somatic mutation can make clone more
suscetible to acquire a JAK2 mutation with subsequent development of MPN, in very
recent study of MPNs transforming to acute leukemia interesting novel insights into
the molecular pathogenesis of these event have been made. Acute leukemia following
JAK2+MPN can be JAK2-mutant and JAK2-wild type. Patterns of second hits, however,
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4 th Croatian Congress of Clinical Cytology / 1 st Croatian Symposium of Analytical Cytology / 2 nd Croatian Symposium of Cytotechnology