Cytogenetic evolution in myeloproliferative neoplasms with different molecular abnormalities

2019 ◽  
Vol 77 ◽  
pp. 120-128
Author(s):  
Seon Young Kim ◽  
Mosae Koo ◽  
Yumi Park ◽  
Hyunjin Kim ◽  
Qute Choi ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Molecular Abnormalities ◽  
Cytogenetic Evolution

Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms

Blood ◽  
2011 ◽  
Vol 117 (9) ◽  
pp. 2700-2707 ◽  
Author(s):  
Luciana Teofili ◽  
Maurizio Martini ◽  
Maria Grazia Iachininoto ◽  
Sara Capodimonti ◽  
Eugenia Rosa Nuzzolo ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Signal Transducer ◽  
Cell Compartment ◽  
Molecular Abnormalities ◽  
Endothelial Colony Forming Cells ◽  
Molecular Abnormality ◽  
Thrombotic Complications ◽  
Human Androgen Receptor

Abstract In this study we investigated whether neoplastic transformation occurring in Philadelphia (Ph)–negative myeloproliferative neoplasms (MPNs) could involve also the endothelial cell compartment. We evaluated the level of endothelial colony-forming cells (E-CFCs) in 42 patients (15 with polycythemia vera, 12 with essential thrombocythemia, and 15 with primary myelofibrosis). All patients had 1 molecular abnormality (JAK2V617F or MPLW515K mutations, SOCS gene hypermethylation, clonal pattern of growth) detectable in their granulocytes. The growth of colonies was obtained in 22 patients and, among them, patients with primary myelofibrosis exhibited the highest level of E-CFCs. We found that E-CFCs exhibited no molecular abnormalities in12 patients, had SOCS gene hypermethylation, were polyclonal at human androgen receptor analysis in 5 patients, and resulted in JAK2V617F mutated and clonal in 5 additional patients, all experiencing thrombotic complications. On the whole, patients with altered E-CFCs required antiproliferative therapy more frequently than patients with normal E-CFCs. Moreover JAK2V617F-positive E-CFCs showed signal transducer and activator of transcription 5 and 3 phosphorylation rates higher than E-CFCs isolated from healthy persons and patients with MPN without molecular abnormalities. Finally, JAK2V617F-positive E-CFCs exhibited a high proficiency to adhere to normal mononuclear cells. This study highlights a novel mechanism underlying the thrombophilia observed in MPN.

scholarly journals Myelodysplastic Syndrome/Acute Myeloid Leukemia Arising in Idiopathic Erythrocytosis

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Stephen E. Langabeer ◽  
Eibhlin Conneally ◽  
Catherine M. Flynn
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Thrombotic Event ◽  
Molecular Abnormalities ◽  
Serum Erythropoietin Level ◽  
Exon 9 ◽  
Next Generation Sequencing Ngs ◽  
Idiopathic Erythrocytosis ◽  
Acute Myeloid

The term “idiopathic erythrocytosis (IE)” is applied to those cases where a causal clinical or pathological event cannot be elucidated and likely reflects a spectrum of underlying medical and molecular abnormalities. The clinical course of a patient with IE is described manifesting as a persistent erythrocytosis with a low serum erythropoietin level, mild eosinophilia, and with evidence of a thrombotic event. The patient subsequently developed a myelodysplasic syndrome (MDS) and acute myeloid leukemia (AML), an event not observed in erythrocytosis patients other than those with polycythemia vera (PV). Application of a next-generation sequencing (NGS) approach targeted for myeloid malignancies confirmed wild-type JAK2 exons 12–15 and identified a common SH2B3 W262R single-nucleotide polymorphism associated with the development of hematological features of myeloproliferative neoplasms (MPNs). Further NGS analysis detected a CBL L380P mutated clone expanding in parallel with the development of MDS and subsequent AML. Despite the absence of JAK2, MPL exon 10, or CALR exon 9 mutations, a similarity with the disease course of PV/MPN was evident. A clonal link between the erythrocytosis and AML could be neither confirmed nor excluded. Future molecular identification of the mechanisms underlying IE is likely to provide a more refined therapeutic approach.

Calr Is up-Regulated in Patients with Essential Thrombocythemia Independently from Calr and JAK2 Mutations

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5581-5581
Author(s):  
Lilia Brown ◽  
Ciaren Graham ◽  
Ciro Rinaldi
Keyword(s):  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Over Expression ◽  
Molecular Abnormalities ◽  
Mutational Status ◽  
Significant Difference ◽  
Exon 9 ◽  
Calr Mutations

Abstract Somatic mutations in exon 9 of calreticulin (CALR) gene were recently discovered in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) lacking JAK2 and MPL mutations, and absent in patient with polycythemia vera (PV). Among patients with ET or PMF with un-mutated JAK2 or MPL, CALR mutations were detected in 67% of those with ET and 88% of those with primary PMF. Several types of insertions or deletions were identified and all resulted in a frameshift in exon 9 generating a novel C-terminal peptide in the mutant CALR protein. Over expression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with myeloproliferative neoplasms carrying CALR mutations present with higher platelet counts and lower haemoglobin levels than patients with mutated JAK2. Studies suggest these patients have a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. We analysed by Real Time PCR, CALR expression in peripheral blood (PB) of 38 patients affected by ET, 17 JAK2 mutated (45%), 4 CALR (10.5%) mutated, 1 MPL mutated (3%) and 14 with no apparent molecular abnormalities. These were compared with a cohort of healthy volunteers. We found a significant over expression of CALR (median 5.15; range 1.13-270.08) comparing with controls (median 0.38, range 0.18-1). CALR mRNA expression is independent from the CALR mutational status. No significant difference was found comparing CALR expression in CALR mutated (median 4.9, range 1.51-37.14) and CALR/JAK2 un-mutated patients (4.68, range 1.51-28.71). CALR up-regulation is not mutually exclusive with JAK2 mutations; no difference was seen in CALR mRNA between JAK2 mutated (median 5.09, range 1.13-270) and wild type ET patients (median 5.08, range 1.51-37). There was no significant difference when we correlated CALR expression with PLT counts, spleen size or type of cytoreductive therapy. A larger cohort of patients is required to confirm these preliminary findings. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4480-4485 ◽  
Author(s):  
Su-Jiang Zhang ◽  
Raajit Rampal ◽  
Taghi Manshouri ◽  
Jay Patel ◽  
Nana Mensah ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Myeloproliferative Neoplasms ◽  
Therapeutic Approaches ◽  
Leukemic Transformation ◽  
Genetic Studies ◽  
Molecular Abnormalities ◽  
Genetic Abnormalities ◽  
Recurrent Mutations ◽  
De Novo Aml

Abstract Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high-throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (P = .05). Importantly, SRSF2 mutations are associated with worsened overall survival in MPN patients who undergo LT in univariate (P = .03; HR, 2.77; 95% CI, 1.10-7.00) and multivariate analysis (P < .05; HR, 2.11; 95% CI, 1.01-4.42). These data suggest that SRSF2 mutations contribute to the pathogenesis of LT and may guide novel therapeutic approaches for MPN patients who undergo LT.

Insights into the Molecular Genetics of Myeloproliferative Neoplasms

2012 ◽  
pp. 411-418
Author(s):  
Huong (Marie) Nguyen ◽  
Jason Gotlib
Keyword(s):  
Molecular Genetics ◽  
Myeloproliferative Neoplasms ◽  
Gene Mutations ◽  
Population Level ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Common Finding ◽  
Control Of Gene Expression ◽  
Disease Evolution ◽  
Molecular Abnormalities

Overview: The molecular biology of the BCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) has witnessed unprecedented advances since the discovery of the acquired JAK2 V617F mutation in 2005. Despite the high prevalence of JAK2 V617F in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), and the common finding of dysregulated JAK-STAT signaling in these disorders, it is now appreciated that MPN pathogenesis can reflect the acquisition of multiple genetic mutations that alter several biologic pathways, including epigenetic control of gene expression. Although certain gene mutations are identified at higher frequencies with disease evolution to the blast phase, MPN initiation and progression are not explained by a single, temporal pattern of clonal changes. A complex interplay between acquired molecular abnormalities and host genetic background, in addition to the type and allelic burden of mutations, contributes to the phenotypic heterogeneity of MPNs. At the population level, an inherited predisposition to developing MPNs is linked to a relatively common JAK2-associated haplotype (referred to as ‘46/1’), but it exhibits a relatively low penetrance. This review details the current state of knowledge of the molecular genetics of the classic MPNs PV, ET, and PMF and discusses the clinical implications of these findings.

scholarly journals Genomic trajectory in leukemogenesis of myeloproliferative neoplasms: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yujie Chen ◽  
Rafee Talukder ◽  
Brian Y. Merritt ◽  
Katherine Y. King ◽  
Marek Kimmel ◽  
...  
Keyword(s):  
Case Report ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Genomic Data ◽  
Myelogenous Leukemia ◽  
Driver Mutations ◽  
Ancestral Reconstruction ◽  
Hematopoietic Stem ◽  
Molecular Abnormalities

Abstract Background We report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low. Genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms are important contributors to disease acceleration. Case presentation A 78-year-old Caucasian female originally treated for stable ET, underwent disease acceleration and transition to myeloid sarcoma and B-cell ALL. Genomic reconstruction based on targeted sequencing revealed the presence of a large del(5q) in all three malignancies and somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency. We propose that the combination of genetic and molecular abnormalities led to hematopoietic stem cell (HSC) injury and disease progression through sub-clone branching. We hypothesize that ancestral reconstruction of genomic data is a useful tool to uncover subclonal events leading to transformation. Conclusions The use of ancestral reconstruction of genomic data sheds light on the unique clinical scenario described in this case report. By determining the mutational profile of tumors at several timepoints and deducing the most parsimonious relationship between them, we propose a reconstruction of their origin. We propose that blast progression originated from subclonal events with malignant potential, which coexisted with but did not originate from JAK2 p.V617F-positive ET. We conclude that the application of genomic reconstruction enhances our understanding of leukemogenesis by identifying the timing of molecular events, potentially leading to better chemotherapy choices as well as the development of new targeted therapies.

scholarly journals Emerging treatments for classical myeloproliferative neoplasms

Blood ◽  
2017 ◽  
Vol 129 (6) ◽  
pp. 693-703 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Claire N. Harrison
Keyword(s):  
Clinical Trials ◽  
Myeloproliferative Neoplasms ◽  
Phase 1 ◽  
Cardiovascular Complications ◽  
Jak2 Inhibitor ◽  
Molecular Abnormalities ◽  
Emerging Treatments ◽  
Novel Target ◽  
Current Guidelines

Abstract There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

scholarly journals Myeloid neoplasms with eosinophilia

Blood ◽  
2017 ◽  
Vol 129 (6) ◽  
pp. 704-714 ◽  
Author(s):  
Andreas Reiter ◽  
Jason Gotlib
Keyword(s):  
De Novo ◽  
Myeloproliferative Neoplasms ◽  
Disease Free Survival ◽  
World Health ◽  
Hematopoietic Stem ◽  
Chronic Eosinophilic Leukemia ◽  
Molecular Abnormalities ◽  
Myeloid Neoplasms ◽  
Variable Sensitivity ◽  
Health Organization

Abstract Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases generated by dysregulated fusion tyrosine kinase (TK) genes is recognized by the World Health Organization (WHO) category, “Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.” In addition to myeloproliferative neoplasms (MPN), these patients can present with myelodysplastic syndrome/MPN, as well as de novo or secondary mixed-phenotype leukemias or lymphomas. Eosinophilia is a common, but not invariable, feature of these diseases. The natural history of PDGFRA- and PDGFRB-rearranged neoplasms has been dramatically altered by imatinib. In contrast, patients with FGFR1 and JAK2 fusion TK genes exhibit a more aggressive course and variable sensitivity to current TK inhibitors, and in most cases, long-term disease-free survival may only be achievable with allogeneic hematopoietic stem cell transplantation. Similar poor prognosis outcomes may be observed with rearrangements of FLT3 or ABL1 (eg, both of which commonly partner with ETV6), and further investigation is needed to validate their inclusion in the current WHO-defined group of eosinophilia-associated TK fusion-driven neoplasms. The diagnosis chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is assigned to patients with MPN with eosinophilia and nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts. Myeloid mutation panels have identified somatic variants in patients with a provisional diagnosis of hypereosinophilia of undetermined significance, reclassifying some of these cases as eosinophilia-associated neoplasms. Looking forward, one of the many challenges will be how to use the results of molecular profiling to guide prognosis and selection of actionable therapeutic targets.

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