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Haematological Malignancies

compared with patients with heterozygous JAK2V617F or wild-type JAK2 genes.18

No disease progression was observed between the

JAK2V617F(-) chronic phase and JAK2V617F(+) blast phase of MPN. Additionally, several other groups have reported a decrease in allelic burden or even a complete disappearance of JAK2V617F at the time of leukaemic transformation.19–21

This is in accordance with Cedars-Sinai

Medical Center findings showing that 18% of chronic MPN samples that were initially positive for either heterozygous or homozygous JAK2V617F became negative for these abnormalities in the blast phase.18

Taken together, the initial aberrant clone of MPN cells may be

JAK2V617F(-) with a higher propensity to undergo clonal evolution, whereas this evolution particularly favours the clone acquiring the JAK2V617F during the chronic phase of MPN. Therefore, the presence of this mutation does not appear to be a prerequisite for the leukaemic transition of MPN, suggesting that additional genetic events are required for full transformation.

One of the molecular mechanisms associated with leukaemic evolution was identified almost two decades ago in a relatively small cohort of MPN patients.22,23

Aberrations of the tumour suppressor

gene TP53 were associated with prior exposure of these patients to genotoxic agents and leukaemic evolution to MPN blast phase. These individuals had mainly been treated with alkylating agents, including chlorambucil and busulfan, as well as radio-therapeutic regimens (e.g. 32P). Both therapies are known to cause DNA damage together with a significant rate of TP53 aberrations.24

It was also noted in

patients who underwent leukaemic evolution that either loss of heterozygosity (LOH) at 17p or mutation of TP53 was related to prior exposure to hydroxyurea, a non-alkylating agent.25,26

However, large

prospective studies of MPN patients concluded that the leukaemogenic potential of this cytoreductive compound by itself is low, whereas the risk increases when hydroxyurea is combined with other chemotherapeutic drugs known to damage DNA.7,27,28 Nevertheless, individuals with MPN who progress to AML may have an aberrant TP53 gene in the absence of exposure to a known mutagen. This is consistent with TP53 alterations being associated with the clonal evolution of many other types of cancers.29

Missense mutations involving the dominantly acting RAS gene family and their signal transduction pathway occur frequently in de novo AML.30

They also occur in chronic myelomonocytic leukaemia (CMML) and juvenile myelomonocytic leukaemia (JMML),31

two chronic

myeloid diseases close to but separate from MPN. Mutations in RAS have also been reported in some cases during the chronic phase of PMF, but not in PV or ET.32,33

Although oncogenic RAS expression

is associated with pronounced proliferation in myeloid lineage cells, transition from MPN to AML is only rarely associated with a RAS mutation.22,23,32–34

Our Cedars-Sinai Medical Center team performed a high-density single nucleotide polymorphism (SNP)-array analysis in a large cohort of 148 patients in the chronic or blast phase of MPN to obtain a profile of genomic alterations and gain more insight into the molecular processes of leukaemic transformation.18

Confirming the hypothesis that evolution

from MPN to leukaemia is accompanied by the acquisition of additional genomic lesions, two to three times more aberrations were detected in the blast phase compared with the chronic phase of MPN, independently of JAK2V617F. Notably, ET patients had fewer alterations in their chronic-phase samples compared with the PV and PMF cases, whereas the number was comparable in all three MPN subgroups


The identification of novel genetic lesions in MPN will probably not only provide new specific diagnostic, prognostic and therapeutic tools, but also increase understanding of the pathogenesis of the disease and its potential acceleration to AML. Recently, TET2, a member of the ten-eleven-translocation (TET) family of genes, has been found to be mutated in various haematopoietic disorders.5,48

TET2 mutational

frequencies did not differ across the MPN subcategories (13–17%) and appeared independently of JAK2V617F. Comparable to family member TET1, TET2 inactivation may have epigenetic consequences that deregulate genes involved in early haematopoiesis as well as in myeloid differentiation.49

While mutant TET2 may co-operate with other

mutated genes to induce AML, the potential value of the mutation as a prognostic tool appears to be low, since no correlation has been found between the presence of mutant TET2 and survival or leukaemic transformation.48

after their transformation. Altered regions commonly occurred on chromosomes 12p (ETV6) and 21q (RUNX1) as well as on 17p (TP53). These genes are known to be involved in the development of de novo as well as secondary AML following myelodysplastic syndrome.35–38


was shown in two case studies that a relatively high number of MPN patients (28 and 37.5%, respectively) acquired a mutation in the RUNX1 gene at the time of disease transformation.26,34

Notably, transduction of

an expression vector carrying mutant RUNX1 into CD34+ cells from MPN patients markedly promoted their proliferation, independently of the presence of JAK2V617F.34

Moreover, our group found gain of

chromosomal material at 8q24.21 (c-MYC), including trisomy 8, almost exclusively in the JAK2V617F(-) transformed samples.18

This suggests

that the increased oncogenic activity of c-MYC is associated with a strong selection of leukaemic clones that can almost completely displace the myeloproliferative compartment with the JAK2 gain-of- function mutation.18

In addition to aberrations involving known oncogenes (c-MYC) or tumour suppressor genes (ETV6, TP53, RUNX1) with already-established leukaemogenic potential, frequently altered regions were detected by SNP-Chip on chromosomes 1q, 7q, 16q, 19p and 21q in MPN blast-phase samples, which may harbour promising new candidate genes.18

Abnormalities involving chromosome 7 are frequently

and the CUTL1 gene encodes for a CUT family member of the homeodomain proteins that can repress the expression of developmentally regulated myeloid genes.43

detectable in de novo and secondary AML. Preceding studies have found a critical breakpoint region involving a locus at centromeric band 7q22, whereas the telomeric breakpoint varies from q32 to q36.39–41 Interestingly, the minimal deleted region in our SNP-array study was located at 7q22.1, encompassing only two target genes: SH2B2 and CUTL1. SH2B2 regulates and enhances JAK2-mediated cellular responses,42

Moreover, genome-wide

inspection for minimal regions of duplications/amplifications revealed several interesting genes including PIN1, ICAM1 and CDC37 on 19p as well as ERG on 21q. Whereas the latter three targets have been shown to possess potential pro-growth activity in de novo AML and/or myelodysplastic syndrome,44–46

PIN1 is known to be overexpressed in a

variety of cancers. It may act as an oncogene via promotion of cell-cycle progression and proliferation.47

However, whether such

lesions impart disease-promoting activity or reflect genetic instability during clonal progression in MPN is currently not delineated.

The ASXL1 gene is mutated in approximately 20% of chronic- or blast-phase MPN cases. Analysis of serial samples from patients with MPN that evolved into AML demonstrated that these mutations were always present during the chronic phase of the


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