Incidence of Early Thrombosis in Myeloproliferative Neoplasms (MPN): A Prospective Analysis from the Gruppo Laziale of Ph-Negative MPN

Abstract Background Thrombotic episodes are the major complication in the follow-up of Philadelphia negative Myeloproliferative Neoplasms (MPN), with high morbidity and mortality, as reported in several retrospective studies. At present, however, few prospective data are available on the early incidence of these complications. Methods To address this issue, we report on 1087 patients [M/F 508/579, median age 67.6 years, interquartile range (IQR) 55.2 - 75.9] with newly diagnosed MPN enrolled in the prospective database of our regional cooperative group since January 2011. Of them, 571 (52.5%) had Essential Thrombocythemia (ET), 303 (27.9%) Polycythemia Vera (PV) and 213 (19.6%) Primary Myelofibrosis (PMF). The main clinical features at diagnosis of the whole cohort and according to the different MPNs are reported in the Table 1. Results On the whole, 22 episodes of thrombotic complications were reported in 1087 patients (2.0%) at a median interval from diagnosis of 18.2 months (IQR 7.4 - 29.7): in particular, 15 (68.1%) were arterial (8 cerebral, 2 coronaric, 4 in the lower limbs, 1 splancnic) and 7 (31.9%) venous (5 in the lower limbs and 2 in the upper limbs). As to the incidence of early thrombosis in the different MPNs, they were 13/571 (2.2%) in ET patients, 5/303 (1.6%) in PV patients and 4/213 (1.8%) in PMF patients (p=0.810): median time from diagnosis to thrombotic event was also similar in the 3 MPNs (p=0.311). The 4-year cumulative Thrombosis-Free Survival (TFS) of the whole cohort was 97.3% (95%CI 96.0 - 98.6): there was no difference among the 3 MPNs as to 4-year TFS [96.7% (95%CI 94.8 - 98.6) in ET, 97.8% (95%CI 95.9 - 99.7) in PV and 98.7% (95%CI 96.9 - 100) in PMF, respectively, p=0.668). Several clinical features at diagnosis (age, gender, Hb levels, WBC and PLT counts, spleen enlargement, JAK-2 V617F mutation and previous thrombotic events) were evaluated for a role in predicting thrombotic events: only age (p=0.009) and previous thrombotic events (p=0.009) were significant. Conclusions The incidence of early thrombosis seems low in the first 4 years after diagnosis of MPN based on our prospective database, without any difference among ET, PV and PMF: it is worth of note that only age and previous thrombotic events had a predictive role, thus confirming many retrospective reported data and reinforcing the prognostic value of old scoring system for thrombotic risk in MPN. Table 1 Table 1. Disclosures Breccia: Ariad: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

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Thrombotic Risk Detection in Patients with Polycythemia Vera: The Predictive Role of DNMT3A/TET2/ASXL1 Mutations

Cancers ◽

10.3390/cancers12040934 ◽

2020 ◽

Vol 12 (4) ◽

pp. 934 ◽

Cited By ~ 2

Author(s):

Adrián Segura-Díaz ◽

Ruth Stuckey ◽

Yanira Florido ◽

Jesús María González-Martín ◽

Juan Francisco López-Rodríguez ◽

...

Keyword(s):

Polycythemia Vera ◽

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

Primary Myelofibrosis ◽

Case Control ◽

Vascular Events ◽

Thrombotic Risk ◽

Initial Cohort ◽

Predictive Role ◽

Next Generation Sequencing Ngs

The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort of 68 patients with myeloproliferative neoplasms (MPN). As expected, the presence of mutations in DNMT3A, TET2, and ASXL1 (DTA genes) was positively associated with age for the whole cohort (p = 0.025, OR: 1.047, 95% CI: 1.006–1.090). Also, while not related with events in the whole cohort, DTA mutations were strongly associated with the development of vascular events in PV patients (p = 0.028). To confirm the possible association between the presence of DTA mutation and thrombotic events, we performed a case-control study on 55 age-matched patients with PV (including 12 PV patients from the initial cohort, 25 with event vs. 30 no event). In the age-matched case-control PV cohort, the presence of ≥1 DTA mutation significantly increased the risk of a thrombotic event (OR: 6.333, p = 0.0024). Specifically, mutations in TET2 were associated with thrombotic events in the PV case-control cohort (OR: 3.56, 95% CI: 1.15–11.83, p = 0.031). Our results suggest that pathogenic DTA mutations, and particularly TET2 mutations, may be an independent risk factor for thrombosis in patients with PV. However, the predictive value of TET2 and DTA mutations in ET and PMF was inconclusive and should be determined in a larger cohort.

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Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study

Hematology Reports ◽

10.4081/hr.2019.8281 ◽

2019 ◽

Vol 11 (4) ◽

Cited By ~ 2

Author(s):

Vincenzo Accurso ◽

Marco Santoro ◽

Simona Raso ◽

Angelo Davide Contrino ◽

Paolo Casimiro ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Clinical Manifestations ◽

Primary Myelofibrosis ◽

Thrombotic Risk ◽

Single Center Study ◽

The Impact ◽

The Relationship

Splenomegaly is one of the major clinical manifestations of primary myelofibrosis and is common also in other chronic Philadelphia-negative myeloproliferative neoplasms, causing symptoms and signs and affecting quality of life of patients diagnosed with these diseases. We aimed to study the impact that such alteration has on thrombotic risk and on the survival of patients with essential thrombocythemia and patients with Polycythemia Vera (PV). We studied the relationship between splenomegaly (and its grade), thrombosis and survival in 238 patients with et and 165 patients with PV followed at our center between January 1997 and May 2019.

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Thrombosis in MPN with Thrombocythemia Is Associated with Higher Platelet Count At the Time of the Event: Data From the Czech Registry of Patients Treated with Anagrelide,

Blood ◽

10.1182/blood.v118.21.3857.3857 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3857-3857

Author(s):

Jiri Schwarz ◽

Miroslav Penka ◽

Petra Ovesna ◽

Olga Cerna ◽

Yvona Brychtova ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

Jak2 V617f ◽

Protein C Deficiency ◽

Thrombotic Risk ◽

Female Ratio ◽

Platelet Counts ◽

Cell Counts ◽

Registry Entry

Abstract Abstract 3857 Background: Recent studies of prognostic parameters in Ph- myeloproliferative neoplasms with thrombocythemia (MPN-t) indicate that WBC counts at diagnosis, rather than platelet (Plt) counts, determine the risk of thrombosis. We have studied these and other risk parameters in our patient cohort. Patients: 843 prospectively assigned patients from the Czech segment of the International registry of patients treated with anagrelide (ANG; Thromboreductin®) were studied. The male: female ratio was 2:3, the median age was 51 (0–96) years. The majority of patients (68.1%) was pretreated by other cytoreducing drugs. According to PVSG criteria, the diagnoses were the following: essential thrombocythemia – 569, primary myelofibrosis – 155, polycythemia vera – 92, or other – 27 patients. Data from the time of diagnosis, from the time of registry entry (at the start of ANG therapy) and from the time of the thrombotic event were evaluated. The median follow-up since registry entry was 33 (0–117) months and the follow-up comprised 2505 patient-years. All patients were treated with ANG and in 80% of follow-up reports, acetylsalicylic acid (ASA) was mentioned to be given in parallel. In 18% of entries (from registration and follow-up), administration of another cytoreducing drug (mainly hydroxyurea or interferon) in combination with ANG was noted. Results: Of 449 thrombotic events reported, 335 occurred in history (i.e. before registry entry) and 114 during follow-up. The numbers of arterial, venous, and microcirculatory events in history were 147, 124 and 64, respectively. Of the 114 thrombotic events in 88 patients during follow-up (3.79 events/100 patient-years), 45 were classified as major. There were 61 arterial, 16 venous and 37 microcirculatory events. ANG ± ASA therapy dramatically decreased the number of venous events (7.8-fold), while arterial and microcirculatory events were reduced 2.4-fold and 1.7-fold, respectively. At diagnosis, the strongest predictors of all thrombotic events jointly were JAK2 V617F mutation (P=0.001), hereditary or acquired thrombophilia (P<0.001), hypertension (P=0.006), smoking (P=0.02) and diabetes mellitus (P=0.04). Also previous thrombosis predicted a subsequent thrombotic event (P=0.002). Age >65 yrs was a less powerful predictor (P=0.08). WBC and hematocrit levels positively correlated with the thrombotic risk (P=0.002 and P=0.006, respectively), whereas Plt counts correlated inversely with all thrombotic events (P=0.012) but correlated positively with microcirculatory events (P=0.01). Some of the factors (age, hypertension, diabetes, and smoking) powerfully predicted rather arterial events, whereas others (f.V “Leiden” mutation, protein C deficiency, elevated f.VIII levels, presence of antiphospholipid antibodies) were connected preferentially with venous events. However, when full blood cell counts from the time of the thrombotic events were studied and compared to mean levels of all entries during follow-up, we could detect higher platelet counts at the time of the thrombotic event (454 vs 420 G/L, P=0.007), while we could not demonstrate any significance of the WBC counts at the time of the event. The correlation of the Plt count was marked in all types of events and was most conspicuous in microcirculatory events. Thrombotic events during follow-up were also associated with lack of ASA therapy: only 6/16 (37.5%) patients at the time of the venous event, 35/61 (57.4%) patients at the time of the arterial event and 11/37 (29.7%) patients at the time of the microcirculatory event received ASA therapy (whereas ASA administration was reported in 80.0% of follow-up entries). Conclusions: The current study indicates that during ANG ± ASA therapy, the incidence of thrombosis is very low in MPN-t and especially the rate of venous events is extraordinarily low. The predictors of the thrombotic events are similar as previously published by others. Above that, we have proven the usefulness of detection of the so-called thrombophilic states. However, in contrast with the prevailing current opinion, we have shown that higher platelet counts (and not WBC counts) are important at the time of thrombosis, albeit at diagnosis the Plt counts may inversely and WBC counts positively correlate with the thrombotic risk. This discrepancy may result from treatment: patients with higher Plt counts at diagnosis may receive more cytoreducing and/or antiaggregation therapy. Disclosures: Schwarz: AOP Pharmaceuticals: Consultancy.

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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 ◽

10.1182/blood.v128.22.5473.5473 ◽

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.

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Nonfamilial,MPLS505N-Mutated Essential Thrombocythaemia

Case Reports in Hematology ◽

10.1155/2013/729327 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Ruth Morrell ◽

Stephen E. Langabeer ◽

Liam Smyth ◽

Meegahage Perera ◽

Gerard Crotty

Keyword(s):

Bone Marrow ◽

Clinical Features ◽

Clinical Course ◽

Myeloproliferative Neoplasms ◽

Significant Proportion ◽

Essential Thrombocythaemia ◽

Bone Marrow Fibrosis ◽

Thrombotic Risk ◽

Exon 10 ◽

Marrow Fibrosis

Mutations ofMPLare present in a significant proportion of patients with the myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF), and essential thrombocythaemia (ET). The most frequent of these mutations, W515L and W515K, occur in exon 10 ofMPL, which encodes the receptor for thrombopoietin. Another exon 10 mutation,MPLS505N, has been shown to be a founder mutation in several pedigrees with familial thrombocythaemia where it is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Rare cases of sporadic, nonfamilial,MPLS505N MPN have been documented, but the presenting laboratory and clinical features have not been described in detail. The diagnosis and clinical course of a case ofMPLS505N-positive MPN are presented with diagnostic features and treatment response resembling typical ET but with evidence of increasing bone marrow fibrosis. Further MPN cases possessing this genotype require reporting in order to ascertain whether any particular morphological or clinical features, if present, determine clinical course and aid the refinement of therapeutic options.

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Incidence and Impact of Activating Mutations of the RAS-RAF-MEK-ERK Pathway in Patients with Philadelphia-Negative (Ph-negative) Myeloproliferative Neoplasms (MPNs) and Myelodysplastic/Myeloproliferative Disorders–Unclassified (MDS/MPD-U)

Blood ◽

10.1182/blood.v124.21.3172.3172 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3172-3172

Author(s):

Fabio PS Santos ◽

Bianca Lisboa ◽

Tarcila S Datoguia ◽

Ricardo Helman ◽

Welbert Oliveira Pereira ◽

...

Keyword(s):

Disease Progression ◽

Clinical Features ◽

Double Mutant ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Allogeneic Transplantation ◽

Driver Mutations ◽

Erk Pathway ◽

Braf Mutations ◽

Activating Mutations

Abstract Introduction: Mutations that activate the RAS-RAF-MEK-ERK pathway have long been known to occur in patients with solid tumors and hematological malignancies. The most common mutations occur in the Ras family of GTPases (HRAS, NRAS, KRAS) and the Raf family of serine-threonine kinases (ARAF, BRAF, CRAF). In myeloid malignancies, RAS mutations have mainly been described in patients with acute myeloid leukemia, chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome. There are few studies describing the incidence of mutations of the RAS-RAF-MEK-ERK pathway in patients with MPNs other than CMML. Objective: To describe the incidence, clinical features and prognostic impact of Ras and Raf mutations in patients with Ph-negative MPNs and MPN/MDS-U Methods: Paired DNA (sorted CD66b-granulocytes/skin biopsy) from patients with MPNs or MPN/MDS was subjected to whole exome sequencing on a Illumina HiSeq 2000 platform using Agilent SureSelect kit (see our abstract “Whole Exome Sequencing of Myeloproliferative Neoplasms and Myelodysplastic/Myeloproliferative Disorders”). Tumor coverage was 150x and germline coverage was 60x. Somatic variants calls were generated by combining the output of Somatic Sniper (Washington University), Mutect (Broad Institute) and Pindel (Washington University), followed by in-house filters to reduce false positive calls. Statistical calculations were done in Stata, v11.0. Results: We found clonal activating mutations of the RAS-RAF-MEK-ERK pathway in 8 patients (6.7% of cases). Diagnosis included primary myelofibrosis (PMF; N=5), MDS/MPD-U (N=2) and essential thrombocythemia (ET; N=1). Their clinical features are summarized in Table 1 (three of these patients [UPIs #11, #13, #99] are also described in the abstract “Genomic Profile of Patients with Triple Negative (JAK2, CALR and MPL) Essential Thrombocythemia and Primary Myelofibrosis”). There were 7 NRAS mutations and 1 BRAF mutation. In 5 cases the variant allele fraction (VAF) of reads in the tumor sample indicated that the mutation was present in a subclone at the time of sequencing. We next compared the clinical features of these 8 patients with 79 patients (MF=43, ET=35, MDS/MPD=1) who did not harbor these mutations. Patients with NRAS/BRAF mutations had lower hemoglobin (8.3 vs. 11.8 g/dL, p=0.001), higher white blood cell counts (28.37 vs. 7.7 x109/L, p=0.008) and had higher lactate dehydrogenase (1041 vs. 685 IU/L, p=0.02). They also had worse overall survival compared to unmutated cases (Hazard ratio [HR]=11.57; p=0.001). Most patients with NRAS/BRAF mutations had a high number of concomitant driver mutatons (median 5 vs. 1; p<0.0001). When the number of driver mutations was analyzed together with NRAS/BRAF mutations in a Cox model, NRAS/BRAF mutations were no longer independent predictors of survival (HR=1.48; p=0.61). Conclusions: Activating mutations of the RAS-RAF-MEK-ERK pathway occur in 6-7% of patients with Ph-negative MPNs, and they tend to co-occur with a high number of concomitant driver mutations. In most cases the mutation was present in a subclone, suggesting that they are late occurring. Patients with NRAS/BRAF mutations had a trend for worse outcome, but that was mainly dependent on the total number of driver mutations. The activity of MEK and BRAF inhibitors needs to be explored in patients with Ph-negative MPNs who harbor activating mutations of the RAS-RAF-MEK-ERK pathway. Table 1. Clinical features of patients with NRAS/BRAF mutations UPI Diagnosis Mutation VAF Concomitant driver genes and Chromosomal abnormalities Outcomes 7 MF NRAS p.G12S 47% ASXL1, CALR, STAG2, U2AF1 Died from disease progression 11 MF NRAS p.G12R 5% ASXL1, CBL, CUX1 (double mutant), EZH2 Died from disease progression 13 MF NRAS p.G12D 48% ASXL1, DNMT3A, ETV6 (double mutant) JARID2, U2AF1 Died from disease progression 18 MF NRAS p.G13D 25% JAK2, Del(5q) Underwent allogeneic transplantation; disease relapsed day+80; alive 29 MDS/MPD-U BRAF p.D594G 25% JAK2, Del(5q) Transformed to AML; entered CR with induction chemotherapy; underwent allogeneic transplantation; disease relapsed day+35; alive 99 ET NRAS p.G12D 43% ASXL1, CSF3R, STAG2 Alive 109 MF NRAS p.Q61R 19% CALR, DNMT3A, ZRSR2 Alive 122 MDS/MPD-U NRAS p.G12S 7% ASXL1, EZH2 (double mutant), PTPN11, TET2 (double mutant) Transformed to AML; underwent allogeneic transplantation; died on day+58 Disclosures No relevant conflicts of interest to declare.

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The Approach to Thrombosis Prevention across the Spectrum of Philadelphia-Negative Classic Myeloproliferative Neoplasms

Hemato ◽

10.3390/hemato2030025 ◽

2021 ◽

Vol 2 (3) ◽

pp. 392-402

Author(s):

Steffen Koschmieder

Keyword(s):

High Risk ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Primary Myelofibrosis ◽

Thrombotic Risk ◽

Increased Risk ◽

Individualized Approach ◽

Night Sweats ◽

Thrombotic Complications

Patients with myeloproliferative neoplasm (MPN) are potentially facing diminished life expectancy and decreased quality of life, due to thromboembolic and hemorrhagic complications, progression to myelofibrosis or acute leukemia with ensuing signs of hematopoietic insufficiency, and disturbing symptoms such as pruritus, night sweats, and bone pain. In patients with essential thrombocythemia (ET) or polycythemia vera (PV), current guidelines recommend both primary and secondary measures to prevent thrombosis. These include acetylsalicylic acid (ASA) for patients with intermediate- or high-risk ET and all patients with PV, unless they have contraindications for ASA use, and phlebotomy for all PV patients. A target hematocrit level below 45% is demonstrated to be associated with decreased cardiovascular events in PV. In addition, cytoreductive therapy is shown to reduce the rate of thrombotic complications in high-risk ET and high-risk PV patients. In patients with prefibrotic primary myelofibrosis (pre-PMF), similar measures are recommended as in those with ET. Patients with overt PMF may be at increased risk of bleeding and thus require a more individualized approach to thrombosis prevention. This review summarizes the thrombotic risk factors and primary and secondary preventive measures against thrombosis in MPN.

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Prevention and Management of Thrombosis in BCR/ABL-Negative Myeloproliferative Neoplasms

Hämostaseologie ◽

10.1055/a-1334-3259 ◽

2021 ◽

Vol 41 (01) ◽

pp. 048-057

Author(s):

Anna Falanga ◽

Marina Marchetti ◽

Francesca Schieppati

Keyword(s):

Risk Factors ◽

Endothelial Cells ◽

Stem Cell ◽

Management Strategy ◽

Blood Clotting ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Hematopoietic Stem ◽

Thrombotic Risk ◽

Prevention And Treatment

AbstractMyeloproliferative neoplasms (MPNs) are clonal disorders of the hematopoietic stem cell. Classical BCR/ABL-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Thrombotic events are a major cause of morbidity and mortality in these patients. Pathogenesis of blood clotting activation involves various abnormalities of platelets, erythrocytes, and leukocytes, as well as dysfunctions of endothelial cells. Patients with MPN can be stratified in “high risk” or “low risk” of thrombosis according to established risk factors. ET and PV clinical management is highly dependent on the patient's thrombotic risk, and a risk-oriented management strategy to treat these diseases is strongly recommended. In this review, we give an overview of risk factors, pathogenesis, and thrombosis prevention and treatment in MPN.

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Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

Annals of Hematology ◽

10.1007/s00277-021-04615-8 ◽

2021 ◽

Author(s):

Julian Baumeister ◽

Tiago Maié ◽

Nicolas Chatain ◽

Lin Gan ◽

Barbora Weinbergerova ◽

...

Keyword(s):

Gene Expression ◽

Late Stage ◽

Rna Splicing ◽

Bone Marrow Cells ◽

Myeloproliferative Neoplasms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Primary Myelofibrosis ◽

Estrogen Signaling ◽

Therapeutic Modalities

AbstractMyeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing–associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN. Graphical abstract

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

Blood ◽

10.1182/blood-2010-07-297598 ◽

2011 ◽

Vol 117 (9) ◽

pp. 2700-2707 ◽

Cited By ~ 56

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.

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