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Leukaemic Transformation of Philadelphia-chromosome-negative Myeloproliferative Neoplasms

ASXL1 belongs to a three-member family of trithorax and polycomb protein enhancers, which are generally involved in the modulation of development-related genes through chromatin remodelling. The haploin sufficiency of ASXL1 may have a role in the pathogenesis of MPN and other myeloid malignancies, but did not appear to be acquired during leukaemic transformation.6


Since intact isocitrate dehydrogenase (IDH) activity is required for cellular protection from oxidative stress by the generation of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, it is believed that both IDH1 and IDH2 act as tumour suppressors. Recently, a multi-institutional project performed a study on a large number of MPN patients in different stages of the disease, and a relatively infrequent number of IDH1 and IDH2 mutations were found in samples from the chronic phase.51

Gene family members IDH1 and IDH2, which encode enzymes that catalyse oxidative decarboxylation of isocitrate to α-ketoglutarate, have also been found to be mutated in patients with myeloid disorders.7

By contrast, the IDH

mutational rate was significantly more prevalent in the blast phase of MPN, at 21.6%, independent of other known mutations including JAK2, MPL and TET2. Interestingly, the presence of an IDH mutation in MPN blast-phase patients also predicted a worse survival, which strengthens the suggestion of its essential pathogenetic contribution to leukaemic transformation. However, functional studies are needed to define the exact role of TET2, ASXL1 and IDH1/2 in normal and malignant haematopoiesis, and specifically in the transformation from MPN to AML.

Mutations of the c-CBL gene in myeloid disorders are strongly associated with LOH on 11q, and are commonly diagnosed in patients with JMML and CMML.52

However, although MPN shares some clinical

as well as haematological features with these entities, c-CBL mutations and/or 11q LOH are infrequent in MPN samples of either chronic phase or blast phase, suggesting that c-CBL plays only a minor role in the direct process of leukaemic transformation of MPN.18,26,53

Concerning the prognostic impact of genetic lesions, LOH caused by deletion of chromosome 17p (TP53) is significantly associated with a complex karyotype and poor survival in myeloid malignancies, including blast transformation of MPN.36

mutation JAK2V617F is strongly associated with the common 9p CNN-LOH, which uncovered a new paradigm that a dominant oncogenic mutation may be further potentiated by duplication of the mutant allele and/or exclusion of the wild-type allele.54–57


involve chromosomal regions that are also frequently affected by deletions. This may have prognostic implications at least similar to the deletions visible by karyotyping. Using SNP-array analysis as a robust and detailed approach to detect CNN-LOH, we found 9p CNN- LOH with homozygous JAK2 mutation associated with an inferior outcome in MPN blast crisis in comparison with individuals with either heterozygous JAK2V617F or wild-type JAK2.18

In contrast to LOH on

17p, the prognostic impact of 9p CNN-LOH was independent of established risk factors such as -7/7q- or complex karyotype. Although JAK2V617F in association with 9p CNN-LOH appears to have no direct impact on MPN transformation, we suggest that the homozygous driver mutation in combination with additional newly acquired aberrations in terms of an additional hit may influence the clinical course of patients with MPN blast phase. As expected in our SNP-array study, blast-phase patients with loss of chromosomal material on 7q showed poor survival, since this is known to be predictive for rapid progression and reduced response in AML therapy.39–41

Interestingly, MPN blast-phase patients with 7q CNN-LOH had comparable survival rates to those with -7/7q- in their leukaemic cells, which is in accordance with previously published data.58

Recently, copy-number

neutral (CNN)-LOH has been frequently detected in myeloid malignancies. It is defined as the presence of a chromosome pair that derives from only one parent in a diploid individual. It cannot be detected by cytogenetics. Acquired CNN-LOH occurs as a result of a mitotic error in somatic cells. This is an important step in cancer development and progression due to the production of homozygosity (caused by mutated or methylated genes) or an aberrant pattern of imprinting. It is well-known in chronic-phase MPN that the activating

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6. Abdel-Wahab O, Manshouri T, Patel J, et al., Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukaemias, Cancer Res, 2010;70(2):447–52.

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Currently existing models of cancer progression have highlighted both the amplification and/or activation of major oncogenes in promoting the progressive accumulation of genetic abnormalities and the inactivation of specific tumour suppressor genes. Nevertheless, in terms of the variety of detected allelic imbalances and target genes shown to be altered in the literature, the current authors suggest that no obligatory candidate gene or pathway is accountable for causing the transformation of chronic MPN to blast phase. As de novo AML, MPN blast phase appears to be a heterogeneous disease that is likely to have evolved multiple mechanisms to provide a proliferative advantage to the abnormal leukaemic clone. Despite the groundbreaking discovery of the JAK2 or MPL mutations in the majority of patients with MPN, it is becoming increasingly evident that these aberrations do not signify either disease-initiating or leukaemia- promoting events. Besides mutations in TET2 and/or ASXL1 that probably affect the epigenetic landscape in MPN cells, the transforming clone may have to accumulate additional secondary transforming events, including genes such as IDH1/2, ETV6, TP53, RUNX1, RAS and/or c-MYC, as well as chromosomal aberrations. The advances of genetic/epigenetic platforms to study paired MPN samples in chronic phase versus blast phase will identify novel somatic alterations and thereby increase understanding of the leukaemic transformation of Philadelphia-chromosome-negative MPN. n

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