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      Classification and Personalized Prognosis in Myeloproliferative Neoplasms

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          Abstract

          Myeloproliferative neoplasms (MPN), comprising polycythemia vera, essential thrombocythemia and myelofibrosis, are chronic hematological malignancies with variable progression rates. Genomic characterization of MPN patients offers the potential for personalised diagnosis, risk stratification and management. We sequenced coding exons from 69 myeloid cancer genes in 2035 MPN patients, comprehensively annotating driver mutations and copy number changes. We developed a genomic classification for MPNs and multistage prognostic models for predicting individual patient outcomes. Classification and prognostic models were validated on an external cohort. 33 genes carried driver mutations in >4 patients, with JAK2 , CALR or MPL mutations being the sole abnormality in 45% patients. The number of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms and demographic variables independently predicted whether patients were diagnosed with essential thrombocythemia versus polycythemia vera, and chronic phase disease versus myelofibrosis. We defined 8 genomic subgroups, exhibiting distinct clinical phenotypes, including diagnostic blood counts, risk of leukemic transformation and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally-tailored predictions of clinical outcomes in chronic phase MPN or myelofibrosis. Predicted and observed outcomes correlated well using internal cross-validation and an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy. Comprehensive genomic characterization identifies distinct genetic subgroups and provides an MPN classification based on causal biological mechanisms. Integration of genomic data with clinical parameters enables personalised predictions of patient outcome and will support management of MPN patients.

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          Mutations and prognosis in primary myelofibrosis.

          A Vannucchi, T L Lasho, P Guglielmelli … (2013)
          Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.
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            Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms.

            Pontus Lundberg, Axel Karow, Ronny Nienhold … (2014)
            Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by aberrant hematopoietic proliferation and an increased tendency toward leukemic transformation. We used targeted next-generation sequencing (NGS) of 104 genes to detect somatic mutations in a cohort of 197 MPN patients and followed clonal evolution and the impact on clinical outcome. Mutations in calreticulin (CALR) were detected using a sensitive allele-specific polymerase chain reaction. We observed somatic mutations in 90% of patients, and 37% carried somatic mutations other than JAK2 V617F and CALR. The presence of 2 or more somatic mutations significantly reduced overall survival and increased the risk of transformation into acute myeloid leukemia. In particular, somatic mutations with loss of heterozygosity in TP53 were strongly associated with leukemic transformation. We used NGS to follow and quantitate somatic mutations in serial samples from MPN patients. Surprisingly, the number of mutations between early and late patient samples did not significantly change, and during a total follow-up of 133 patient years, only 2 new mutations appeared, suggesting that the mutation rate in MPN is rather low. Our data show that comprehensive mutational screening at diagnosis and during follow-up has considerable potential to identify patients at high risk of disease progression.
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              MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.

              Chong Chen, Yu-Yu Liu, Amy R. Rappaport … (2014)
              Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Title: New England Journal of Medicine
                Abbreviated Title: N Engl J Med
                Publisher: New England Journal of Medicine (NEJM/MMS)
                ISSN (Print): 0028-4793
                ISSN (Electronic): 1533-4406
                Publication date Created: October 11 2018
                Publication date (Print): October 11 2018
                Volume: 379
                Issue: 15
                Pages: 1416-1430
                Affiliations
                [1 ]From the Wellcome–MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University Hospitals NHS Foundation Trust (J.G., E.J.B., A.L.G., C.M., J.C., A.R.G.), Cambridge, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus (J.N., D.C.W., N.A., E.P., G.G., L.O., S.O., J.W.T., A.P.B.,...
                Article
                DOI: 10.1056/NEJMoa1716614
                PMC ID: 7030948
                PubMed ID: 30304655
                SO-VID: afc9d012-557b-4eb3-9802-ecb2674f4dae
                Copyright © © 2018
                License:

                http://www.nejmgroup.org/legal/terms-of-use.htm

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