This page contains a Flash digital edition of a book.
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


disease.6,50


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


CNN-LOH can


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


1. Koppikar P, Levine RL, JAK and MPL mutations in myeloproliferative neoplasms, Acta Haematol, 2008;119(4): 218–25.


2. Levine RL, Gilliland DG, Myeloprolierative disorders, Blood, 2008;112(6):2190–8.


3. Royer Y, Staerk J, Costuleanu M, et al., Janus kinases affect thromboprotein receptor cell surface localization and stability, J Biol Chem, 2005;280:27251–61.


4. Khwaja A, The role of Janus kinases in haemopoiesis and haematological malignancy, Br J Haematol, 2006;134:366–84.


5. Delhommeau F, Dupont S, Della Valle V, et al., Mutation in TET2 in myeloid cancers, N Engl J Med, 2009;360(22):2289–301.


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.


7. Green A, Beer P, Somatic mutations of IDH1 and IDH2 in the


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


leukaemic transformation of myeloproliferative neoplasms, N Engl J Med, 2010;362(4):369–70.


8. Finazzi G, Caruso V, Marchioli R, et al., Acute leukaemia in polycytemia vera: an analysis of 1638 patients entrolled in a prospective observational study, Blood, 2005;105(7):2664–70.


9. Gangat N, Wolanskyj AP, McClure RF, et al., Risk stratification for survival and leukaemic transformation in essential thrombocythemia: a single institutional study of 605 patients, Leukemia, 2007;21(2):270–6.


10. Dupriez B, Morel P, Demory JL, et al., Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system, Blood, 1996;88(3):1013–8.


11. Mesa RA, Li CY, Ketterling RP, et al., Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases, Blood, 2005;105(3):973–7.


12. Tefferi A, Vardiman JW, Classification and diagnosis of


myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms, Leukemia, 2007;22:14–22.


13. Grimwade D, Walker H, Harrison G, et al., The predictive value of hierarchicacl cytogenetic classification in older adults with acute myeloid leukaemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial, Blood, 2001;98(5):1312–20.


14. Larson RA, Is secondary leukaemia an independent poor prognostic factor in acute myeloid leukaemia?, Best Pract Res Clin Haematol, 2007;20(1):29–37.


15. Swolin B, Rödjer S, Westin J, Therapy-related patterns of cytogenic abnormalities in acute myeloid leukaemia and myelodysplastic syndrome post polycythemia vera: single center experience and review of the literature, Ann Hematol, 2008;87(6):467–74.


16. Passamonti F, Rumi E, Pietra D, et al., Relation between JAK2


EUROPEAN ONCOLOGY & HAEMATOLOGY


61


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  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92