scholarly journals Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2100
Author(s):  
Lasse Kjær
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Clinical Intervention ◽  
Driver Mutation ◽  
Response Monitoring ◽  
Driver Mutations ◽  
Clonal Hematopoiesis ◽  
Disease Biology ◽  
Background Population ◽  
The Impact

Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.

Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

2021 ◽  
Vol 41 (03) ◽  
pp. 197-205
Author(s):  
Franziska C. Zeeh ◽  
Sara C. Meyer
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Mutational Analysis ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Standard Of Care ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Therapeutic Decisions ◽  
Jak2 Inhibitors

AbstractPhiladelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

scholarly journals Complex molecular genetic diagnostic algorithm in the diagnosis of myeloproliferative neoplasms

2014 ◽  
Vol 155 (52) ◽  
pp. 2074-2081 ◽  
Author(s):  
Tünde Krähling ◽  
Katalin Balassa ◽  
Nóra Meggyesi ◽  
András Bors ◽  
Judit Csomor ◽  
...  
Keyword(s):  
Triple Negative ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Molecular Techniques ◽  
Janus Kinase ◽  
Driver Mutations ◽  
Similar Distribution ◽  
Janus Kinase 2 ◽  
Chain Reactions ◽  
Thrombopoietin Receptor

Introduction: Mutations in Janus kinase 2, calreticulin and thrombopoietin receptor genes have been identified in the genetic background of Philadelphia chromosome negative, “classic” myeloproliferative neoplasms. Aim: The aim of the authors was to identify driver mutations in a large myeloproliferative cohort of 949 patients. Method: A complex array of molecular techniques (qualitative and quantitative allele-specific polymerase chain reactions, fragment analyzes, high resolution melting and Sanger sequencing) was applied. Results: All 354 patients with polycythemia vera carried Janus kinase 2 mutations (V617F 98.6%, exon 12: 1.4%). In essential thrombocythemia (n = 468), the frequency of V617F was 61.3% (n = 287), that of calreticulin 25.2% (n = 118), and that of thrombopoietin receptor mutations 2.1% (n = 10), while 11.3% (n = 53) were triple-negative. Similar distribution was observed in primary myelofibrosis (n = 127): 58.3% (n = 74) V617F, 23.6% (n = 30) calreticulin, 6.3% (n = 8) thrombopoietin receptor mutation positive and 11.8% (n = 15) triple-negative. Conclusions: The recent discovery of calreticulin gene mutations led to definite molecular diagnostics in around 90% of clonal myeloproliferative cases. Orv. Hetil., 2014, 155(52), 2074–2081.

scholarly journals Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events

2021 ◽  
Vol 5 (18) ◽  
pp. 3515-3527
Author(s):  
Stefan Schmidt ◽  
Dimitri Daniliants ◽  
Elisabeth Hiller ◽  
Eberhard Gunsilius ◽  
Dominik Wolf ◽  
...  
Keyword(s):  
Clinical Data ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Enzyme Linked Immunosorbent Assay ◽  
Thromboembolic Complications ◽  
End Points ◽  
Mutational Status ◽  
Healthy Donors ◽  
History Of ◽  
The Impact

Abstract Morbidity and mortality of Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) are mainly determined by thromboembolic complications. Thrombus formation is facilitated by a neutrophil-specific form of cell death linked to neutrophil extracellular trap (NET) formation (NETosis). Preclinical and clinical data suggested a potential link between NETosis and thrombosis in MPNs. In this study, we aimed to define the impact of NETosis on clinical end points in a large MPN cohort. NETosis was induced in vitro by ionomycin and quantified by enzyme-linked immunosorbent assay–based nucleosome release assays as well as fluorescent staining of free DNA in samples from 103 MPN patients and 28 healthy donors. NETosis rate was correlated with a broad set of clinical data, such as MPN subtype, mutational status, laboratory variables, history of thrombotic events, and treatment types. Triggered NETosis levels were clearly higher in MPN patients than in healthy donors. Positivity for JAK2 V617F or exon 12 as well as CALR mutations correlate with increased NET formation. However, neither JAK2 allelic burden nor history of thromboembolic complication nor the presence of other risk factors for thrombosis (eg, leukocytosis) were associated with the rate of NETosis. In addition, none of the analyzed laboratory parameters nor the type of treatment significantly impacted the rate of NETosis formation. The biology of MPNs has an impact on NET formation because genetic driver mutations favor induction of NETosis, but this does not seems to translate into important clinical end points such as thromboembolic complications. Therefore, NETosis may play a role in facilitating thrombosis, but it is not a sole causative determinant in MPN-associated thrombophilia.

scholarly journals Profile of Myeloproliferative Neoplasms in Kuwait: Population-Based Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5373-5373
Author(s):  
Mazyad Jamal Almazyad ◽  
Aisha S Alwehaib ◽  
Salem Alshemmari
Keyword(s):  
High Risk ◽  
Similar Pattern ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Population Based ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Positive Finding ◽  
Population Based Study ◽  
Arms Pcr

Introduction Myeloproliferative neoplasms (MPNs) are a group of hematopoietic disorders of stem-cell origin, characterized by mutations that disrupt hematopoietic signal-transduction pathways. The Middle East lacks an MPN registry representative of the disease in our area. Here we report on the epidemiology of these neoplasms in our area, including phenotype, clinical features and relevant outcomes. Methods This population-based study reports various demographic characteristics and clinical attributes of all suspected and confirmed MPN patients from all over Kuwait referred to the research hematology lab at Kuwait University & cytogenetic lab in Kuwait Cancer Control Centre (KCCC) during the period from 2007 to 2018. Molecular determination of the patients' driver mutation status currently relies on ARMS-PCR. Confirming a diagnosis follows the WHO criteria, and its refinements, for the diagnosis of MPNs. Data entry and analysis was performed using SPSS (v.22) software. Results Most patients are ≥ 40 years old (79.8%), with a median age of 55 years. Gender distribution is almost equal, with ethnic categorization as Kuwaiti and Non-Kuwaiti showing a similar pattern. ET is the most common diagnosis (40.1%), followed by PRV (32.3%). JAK2 V617F mutation is reported positive in 89.7% of cases, followed by CALR in 8.0% of MPNs. The incidence of MPNs ranged from 0.5 to 2.1 per 100,000 in 2007 through 2018. The lowest rate was recorded in 2007 (0.511) and the highest was observed in 2011 and 2016 (2.417 and 2.101, respectively). The increase in 2011 is likely due to the introduction of a more sensitive technique using ARMS-PCR for the diagnosis of MPNs, whereas the increase in 2017 may be explained by the publication of WHO 2016 modified criteria. Moreover, throughout the years, the distribution of MPNs in different age groups showed similar pattern, with the highest incidence in patients aged ≥ 60. Driver mutations can fit with a general increase in incidence from 2007-2017, which may be attributed to increased awareness among treating physicians asking suspected cases to screen for MPNs using molecular techniques.One hundred and twenty-four (18.5%) cases were documented to have a prior history of thrombosis, with roughly equal distribution between arterial and venous sites. A large proportion (89.5%) of the thrombotic events occurred in those who are ≥ 40 years old, with most events being associated with ET (34.7%) and PRV (33.1%). Almost one-third of cases of thrombosis were associated with undetermined MPN diagnosis. Participating patients were categorized as either low or high risk for thrombotic events, with the latter being defined as age ≥ 55 years and the presence of a previous thrombotic event. The results demonstrate that a total of 46 cases were defined as high risk, most of them being associated with ET (20 cases) and PRV (19 cases). A statistically significant association was reported between gender and site of occurrence of thrombotic events, with males having more arterial thromboses, and females were documented to have more venous thromboses. Conclusion JAK2 V617F driver mutation is the most common positive finding in the participating patients. Roughly one-fifth of the participants encountered thrombotic events, and the site of thrombosis is associated with gender, demonstrating statistical significance. These results should warrant a more thorough evaluation of MPNs in Kuwait to provide a better understanding of its epidemiology. This can be achieved through optimized documentation of patients' data, and testing for additional novel driver mutations and transformation; as well as encourage physicians in primary care centers to refer suspected cases for molecular diagnosis. Disclosures No relevant conflicts of interest to declare.

Patients with myeloproliferative neoplasms (MPN) who later develop ph+ chronic myelogenous leukemia (CML): A case series.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18563-e18563
Author(s):  
Shahina Patel ◽  
Seo-Hyun Kim ◽  
Jamile M. Shammo ◽  
Jerald P. Radich ◽  
Howard R. Terebelo
Keyword(s):  
Lead Time ◽  
Chart Review ◽  
Myeloproliferative Neoplasms ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Case Series ◽  
Myelogenous Leukemia ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
True Incidence

e18563 Background: Myeloproliferative Neoplasms are divided by the presence or absence of the Philadelphia Chromosome. Ph- MPN, typically possess driver mutations of JAK-2, MPL and CALR. CALR is involved with apoptosis and cell proliferation . MPL leads to TPO receptor stimulation and mutations are reported as a known cause of AA. JAK-2 mutations render hematopoietic stem cells more sensitive to growth. Though the true incidence is unknown, there are infrequent reports of pts with ET who later develop CML. CALR, MPL and JAK-2 mutations may have some further role in determining whether these are two separate events or clonally derived. We report three pts with MPN who later developed CML. Methods: Chart Review Results: Pt 1 had ET, diagnosed 21 yrs earlier treated with hydroxyurea. He then developed a rising WBC and platelets which necessitated a marrow which detected Ph+ CML. He was CALR positive. NGS was negative for nondriver mutations. Platelets initially declined from 3 million to 975K with TKI and he achieved a MMR. However, the inability to control his thrombocytosis required the addition of ruxolitinib. Pt 2 was diagnosed with ET and was treated with P32. Nine yrs later CML was diagnosed and TKI administration achieved a MMR. Subsequently, a profound anemia evaluation diagnosed PNH requiring eculizumab without benefit and repeat marrow with NGS revealed a MPLmutation and post-ET myelofibrosis. Pt 3 presented with a JAK-2 positive mutation and Polycythemia Vera. After four yrs of hydroxyurea extreme leukocytosis led to a marrow revealing a diagnosis of Ph+ CML. Dasatinib achieved a prompt MMR. NGS revealed KIT D618 V , coinciding with a diagnosis of systemic mastoytosis (SM). Conclusions: The rare observation of patients with both ET and CML have been reported by others with some recent implications of CALR as a common clone with double-mutant properties of CML. Our patients had a lead time of 21, 9, and 4 yrs, all having different mutations. Pts with MPN who develop unexplained leuko or thrombocytosis should be evaluated for CML.We plan to retrieve archival tissue to perform serial genetic analyses. Further work is required to determine whether these events are stochastic or represents clonal evolution.

Latium (Italy) Epidemiology of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms (MPNs) from 2011 to 2015: A Prospective Analysis from Gruppo Laziale of Ph Negative MPN

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5473-5473
Author(s):  
Marianna De Muro ◽  
Ambra Di Veroli ◽  
Marco Montanaro ◽  
Roberto Latagliata ◽  
Cristina Santoro ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Community Based ◽  
Thrombotic Risk ◽  
Inflammatory Bowel ◽  
Perspective Analysis ◽  
Observation Period

Abstract Background: MPNs including Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), are clonal hematopoietic diseases in which the discovery of molecular driver mutations (JAK2, CALR, MPL) has deeply modified diagnostic approach in recent years. To date available data on epidemiology of MPNs and perspective analysis are rare. Our aim is to study the incidence of MPN Ph negative in a specific region of Italy named Latium and its variability across five years. Moreover we prospectively report the general features of our population. Method: We present here the prospective epidemiologic analysis of 1116 adult patients affected by MPNs (PV=289, ET=550, PMF=209) diagnosed according to 2008 WHO criteria, from January 2011 to December 2015 in 15 hematological Centers (5 academic and 10 community-based Hospitals) in Latium. A total of 289 PV, 550 ET and 209PMF were identified. The overall incidence rate of 289PV was 1.0/105 in 2011 and 2012, 1.1/105 in 2013, 0.9/105 in 2014 and 2015. The overall incidence rate of 550ET was 2.0/105 in 2011, 2.4/105 in 2012, 2.2/105 in 2013, 1.8/105 in 2014 and 1,2/105 in 2015 and the overall incidence rate of 209PMF was 0.7/105 in 2011 and 2012, 1.0/105 in 2013, 0.7/105 in 2014 and 0.5/105 in 2015. We have observed also 63 cases of MPNu (36M/32F) and the incidence rate was 0.3/105 in 2011 and 2012, 0.14/105 in 2013, 0.24/105 in 2014 and 0.22/105 in 2015. Baseline features of PV, ET and PMF patients are summarized in table 1. We have also analyzed the presence of comorbidities including obesity, arhythmia and neoplasia observed at the diagnosis in 1.6, 6.2 and 4% of all population, respectively; thirty-five percent of 1116 pts presented other comorbidities such as diabetes, inflammatory bowel disease, renal and liver failure. As thrombotic risk factors we considered diabetes, dislipidemia, smoke, essential hypertension and thrombophilia observed in 11,8, 16,2, 13,2, 51,7 and 3% of total pts, respectively. Conclusions: We confirm in our prospective observational protocol the overall incidence of MPN Ph negative, previously reported in the literature and the major incidence of male gender in PV and PMF, female in of ET. The annual incidence from 2011-2015 in Latium is remained substantially the same during the observation period. The decreasing trend observed in 2015 is probably due to the different update of some Centers that was done in October 2015 not including patients diagnosed in the last two months. Disclosures Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Breccia:Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria.

Molecular risk stratification of myeloproliferative neoplasms

2020 ◽  
pp. 79-92
Author(s):  
Paola Guglielmelli ◽  
Alessandro M. Vannucchi
Keyword(s):  
Mutational Analysis ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
World Health ◽  
Driver Mutations ◽  
Chronic Myeloproliferative Neoplasms ◽  
Molecular Landscape ◽  
Health Organization ◽  
The Impact ◽  
Risk Categories

Recent advances in understanding the molecular landscape of chronic myeloproliferative neoplasms (MPN) have remarkably improved the diagnostic approach to these disorders. The three phenotypic driver mutations, involving JAK2 (V617F, exon 12 mutations), MPL, and CALR, are major diagnostic criteria in the World Health Organization (WHO) classification, and point to different risk categories. Subclonal mutations in genes of the epigenetic regulation and the spliceosome deserve major prognostication significance and contribute to identify categories of patients with different survival and risk of leukaemia. This chapter will address these aspects and elucidate how mutational analysis may contribute to advanced assessment of MPN patients, as well as its the impact on prognosis for those with MPN.

scholarly journals Is there a gender effect in polycythemia vera?

2020 ◽  
Vol 100 (1) ◽  
pp. 11-25
Author(s):  
Francesca Palandri ◽  
Barbara Mora ◽  
Naseema Gangat ◽  
Lucia Catani
Keyword(s):  
Polycythemia Vera ◽  
Clinical Presentation ◽  
Myeloproliferative Neoplasms ◽  
Treatment Strategies ◽  
Gender Effect ◽  
Thrombotic Risk ◽  
Chronic Myeloproliferative Neoplasms ◽  
Disease Biology ◽  
Systemic Symptoms ◽  
The Impact

AbstractIn recent times, there has been a growing interest in understanding the impact of gender on disease biology and clinical outcomes in Philadelphia-negative chronic myeloproliferative neoplasms. Among those, polycythemia vera (PV) is characterized by increased thrombotic risk, systemic symptoms, and overall reduced survival. Here, we aim to summarize data on whether and to what extent female sex can affect PV biology and outcome. To this end, we will discuss the latest acquisitions in terms of pathogenesis, diagnosis, epidemiology, clinical presentation and symptoms burden, thrombotic risk and related treatment strategies, and prognosis in female patients affected by PV.

scholarly journals Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1962
Author(s):  
Giuseppe G. Loscocco ◽  
Giacomo Coltro ◽  
Paola Guglielmelli ◽  
Alessandro M. Vannucchi
Keyword(s):  
Rna Splicing ◽  
Residual Disease ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Chromatin Modification ◽  
Response To Treatment ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Myeloid Neoplasm ◽  
Molecular Landscape

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the JAK-STAT signaling, which represents a target for therapy. Beyond driver ones, most patients, especially with myelofibrosis, harbor mutations in an array of “myeloid neoplasm-associated” genes that encode for proteins involved in chromatin modification and DNA methylation, RNA splicing, transcription regulation, and oncogenes. These additional mutations often arise in the context of clonal hematopoiesis of indeterminate potential (CHIP). The extensive characterization of the pathologic genome associated with MPN highlighted selected driver and non-driver mutations for their clinical informativeness. First, driver mutations are enlisted in the WHO classification as major diagnostic criteria and may be used for monitoring of residual disease after transplantation and response to treatment. Second, mutation profile can be used, eventually in combination with cytogenetic, histopathologic, hematologic, and clinical variables, to risk stratify patients regarding thrombosis, overall survival, and rate of transformation to secondary leukemia. This review outlines the molecular landscape of MPN and critically interprets current information for their potential impact on patient management.

scholarly journals Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution.

2020 ◽  
Author(s):  
Jyoti Nangalia ◽  
Nicholas Williams ◽  
Joe Lee ◽  
Luiza Moore ◽  
E Baxter ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Myeloproliferative Neoplasms ◽  
Phylogenetic Reconstruction ◽  
Clonal Expansion ◽  
In Utero ◽  
Driver Mutation ◽  
Driver Mutations ◽  
New Paradigm ◽  
Blood Cancer ◽  
Age Related

Abstract Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 448,553 somatic mutations from whole-genome sequencing of 843 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 10 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation in these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition ranging between 4.1 months and 11.4 years across 5 patients. DNMT3A mutations, which are associated with age-related clonal haematopoiesis, were also acquired in utero or childhood, by 7.9 weeks of gestation to 7.8 years across 4 patients. Subsequent driver mutation acquisition was separated by decades. The mean latency between JAK2V617F acquisition and clinical presentation was 34 years (range 20-54 years). Rates of clonal expansion varied substantially (<10% to >200% expansion/year), were affected by additional driver mutations, and predicted latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition very early in life with life-long growth trajectories drive adult blood cancer, providing opportunities for early detection and intervention, and a new paradigm for cancer development.

Sign in / Sign up

Export Citation Format

Share Document