The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes (original) (raw)
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OncoTargets and Therapy
Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by an increased risk of thrombosis and progression to acute myeloid leukemia. MPN are associated with driver mutations in JAK2, CALR and MPL which are crucial for the diagnosis and lead to a constitutive activation of the JAK-STAT signaling, independent of cytokine regulation. Moreover, most patients have concomitant mutations in genes involved in DNA methylation, chromatin modification, messenger RNA splicing, transcription regulation and signal transduction. These additional mutations may arise before, in the context of clonal hematopoiesis of indeterminate potential (CHIP), or after the acquisition of the driver mutation. The clinical phenotype of MPN results from complex interactions between mutations and host factors. The increased application of next-generation sequencing (NGS) techniques to a large series of patients with MPN has expanded the knowledge of mutational landscape and contributed to define the clinical significance of mutations. This molecular information is being increasingly used to refine diagnosis, risk stratification, monitoring of residual disease and response to treatment. ASXL1, SRSF2, EZH2, IDH1/IDH2 and U2AF1 mutations are associated with a more advanced disease and reduced overall survival in primary myelofibrosis (PMF), whereas spliceosome mutations in Polycythemia vera (PV) and essential thrombocythemia (ET) adversely affect both overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival. This review discusses current knowledge of the molecular landscape of MPN, and how the availability of those molecular information may impact patient management.
Genomic analysis of myeloproliferative neoplasms in chronic and acute phases
Haematologica, 2016
Genomic analysis of myeloproliferative neoplasms in chronic and acute phases Myeloproliferative neoplasms (MPNs) are chronic, clonal hematopoietic disorders that include polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). A substantial proportion transforms into acute myeloid leukemia (AML) with a dismal prognosis. 1 Mutually-exclusive hotspot driver mutations in JAK2, CALR, and MPL genes are present in 90% of PV, ET and PMF. The remaining 10% of cases are called triple negatives (TN). Mutations in other genes (e.g., ASXL1, DNMT3A, EZH2, IDH1/2, SH2B3, SRSF2, TET2) are also recurrent in MPNs. 2-5 To better define the genetic events involved in MPN evolution and transformation, 2,3,5,6 we studied 57 MPNs in chronic phase and 38 post-MPN AMLs from the IPC/CRCM Tumor Bank (authorization #AC-2007-33). Patients were appropriately informed and asked to consent in writing, in compliance with French and European regulations. MPN diagnosis was established according to the revised criteria of the World Health Organization. 7 The 57 chronic cases were separated into two groups: 40 without acute evolution, arbitrarily called "steady" MPNs or sMPNs (median follow up was 17.9 years (11-28)); and 17 that transformed to AML, called tMPNs (median time between diagnosis of chronic and acute phases was 8.5 years (1-29)). The latter group had 17 matched post-MPN AML samples among the 38 cases of post-MPN AML. Genomic analysis was carried out for most patients in chronic phase during disease course, not at diagnosis. Median time between diagnosis and sample was 12.9 years (2-24 years) for sMPNs, and 5.7 years (0-25) for tMPNs (Online Supplementary Table S1).
Background The Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) (i.e. essential thrombocythaemia (ET), polycythaemia vera (PV), and primary myelofibrosis (PMF)) are a group of chronic clonal haematopoietic disorders that have the propensity to advance into bone marrow failure or acute myeloid leukaemia; often resulting in fatality. Although driver mutations have been identified in these Ph-negative MPNs, subtype-specific markers of the disease have yet to be discovered. Next-generation sequencing (NGS) technology can potentially improve the clinical management of Ph-negative MPNs by allowing for the simultaneous screening of many disease-associated genes. Methods The performance of a custom, in-house designed 22-gene NGS panel was technically validated using reference standards across two independent replicate runs. The panel was subsequently used to screen a total of 10 clinical MPN samples (ET n = 3, PV n = 3, PMF n = 4). The resulting NGS data was then analysed via ...
HemaSphere, 2019
Purpose of Review To review the impact of next-generation sequencing (NGS) on laboratory approach of myeloproliferative neoplasms (MPNs). Recent Findings Next-generation sequencing has provided valuable information on the mutational landscape of MPNs and has been used for various applications, including diagnosis, risk stratification, monitoring of residual disease or disease progression, and target therapy. Most commonly, targeted sequencing of a panel of genes that have been shown to be recurrently mutated in myeloid neoplasms is used. Although numerous studies have shown the benefit of using NGS in the routine clinical care of MPN patients, the complexity of NGS data and how these data may contribute to the clinical outcome have limited the development of a standard clinical guideline. Summary We review recent literature and discuss how to interpret and use NGS data in the clinical care of MPN patients.
American Journal of Hematology, 2017
Acute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prognostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics, the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P 5 .0001), TET2 (P 5 .011) and SRSF2 (P 5 .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT.. .) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase.
HemaSphere, 2018
Although next-generation sequencing (NGS) has helped characterize the complex genomic landscape of myeloid malignancies, its clinical utility remains undefined. This has resulted in variable funding for NGS testing, limiting its accessibility. At our center, targeted sequencing (TAR-SEQ) using a 54-gene NGS myeloid panel is offered to all new patients referred for myeloid malignancies, as part of a prospective observational study. Here, we evaluated the diagnostic, prognostic, and potential therapeutic utility of clinical grade TAR-SEQ in the routine workflow of 179 patients with myeloproliferative neoplasms (MPN). Of 13 patients with triple negative (TN) MPN, who lacked driver mutations in JAK2, CALR, and MPL, TAR-SEQ confirmed clonal hematopoiesis in 8 patients. In patients with intermediate-risk myelofibrosis (MF), TAR-SEQ helped optimize clinical decisions in hematopoietic cell transplant (HCT)-eligible patients through identifying a high molecular risk (HMR) mutation profile. The presence of an HMR profile favored HCT in 9 patients with intermediate-1 risk MF. Absence of an HMR profile resulted in a delayed HCT strategy in 10 patients with intermediate-2 risk MF, 7 of which were stable at the last follow-up. Finally, TAR-SEQ identified patients with various targetable mutations in IDH1/2 (4%), spliceosome genes (28%), and EZH2 (7%). Some of these patients can be potential candidates for future targeted therapy trials. In conclusion, we have demonstrated that TAR-SEQ improves the characterization of TN MPN, can be integrated in clinical practice as an additional tool to refine decision making in HCT, and has the potential to identify candidates for future targeted therapy trials.
Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms
Leukemia, 2013
on behalf of AGIMM investigators With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2000 cancerassociated genes and microRNAs. The genomic DNA of granulocytes and in vitro-expanded CD3 รพ T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest dynamic international prognostic scoring system (DIPSS)-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing a NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score.
Classification and Personalized Prognosis in Myeloproliferative Neoplasms
The New England journal of medicine, 2018
Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment. We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort. A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced ...
The effects of mutational profiles on phenotypic presentation of myeloproliferative neoplasm subtypes in Bosnia: 18 year follow-up, 2020
The identification of mutually exclusive somatic mutations shared among myeloproliferative neoplasm (MPN) subtypes has provided a powerful tool for studying disease evolution. Clinical features, gene mutations, and survival over 18 years were analyzed in MPN patients. One hundred thirty-eight MPN patients were subcategorized according to MPN subtypes: essential thrombocythemia (ET, n = 41), polycythemia vera (PV, n = 56), primary myelofibrosis (PMF, n = 10), and MPN unclassified (MPN-U, n = 31). Patient characteristics included clinical parameters, overall survival (OS), and mutational status of the Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) genes. We compared hematologic and clinical features of JAK2 V617F-ET vs. CALR-mutated ET vs. JAK2 V617F-PV patients. JAK2 V617F-patients had higher values of erythrocytes, hemoglobin, and hematocrit compared to CALR-mutated patients (p < 0.05). The mutant allele burden in JAK2 V617F-PV and JAK2 V617F-ET patients directly correlated with erythrocyte, hemoglobin, and hematocrit values, but it inversely correlated with platelet count. Thus, mutant allele burden was an indicator of the clinical phenotype in JAK2 V617F-MPN patients. OS was not affected by the mutational status. In general, mutated JAK2, CALR, and MPL genes left specific hematological signatures.