Inflammation as a cause of acute myocardial infarction in patients with myeloproliferative neoplasm

Myeloproliferative neoplasms(MPN)are a group of diseases characterized by the clonal proliferation of hematopoietic progenitor or stem cells.They are clinically classifiable into four main diseases:chronic myeloid leukemia,essential thrombocythemia,polycythemia vera,and primary myelofibrosis.These pathologies are closely related to cardio-and cerebrovascular diseases due to the increased risk of arterial thrombosis,the most common underlying cause of acute myocardial infarction.Recent evidence shows that the classical Virchow triad(hypercoagulability,blood stasis,endothelial injury)might offer an explanation for such association.Indeed,patients with MPN might have a higher number and more reactive circulating platelets and leukocytes,a tendency toward blood stasis because of a high number of circulating red blood cells,endothelial injury or overactivation as a consequence of sustained inflammation caused by the neoplastic clonal cell.These abnormal cancer cells,especially when associated with the JAK2V617F mutation,tend to proliferate and secrete several inflammatory cytokines.This sustains a pro-inflammatory state throughout the body.The direct consequence is the induction of a pro-thrombotic state that acts as a determinant in favoring both venous and arterial thrombus formation.Clinically,MPN patients need to be carefully evaluated to be treated not only with cytoreductive treatments but also with cardiovascular protective strategies.

Budd-Chiari syndrome in myeloproliferative neoplasms:A review of literature

Myeloproliferative neoplasms(MPNs)are defined as clonal disorders of the hematopoietic stem cell in which an exaggerated production of terminally differentiated myeloid cells occurs.Classical,Philadelphia-negative MPNs,i.e.,polycythemia vera,essential thrombocythemia and primary myelofibrosis,exhibit a propensity towards the development of thrombotic complications that can occur in unusual sites,e.g.,portal,splanchnic or hepatic veins,the placenta or cerebral sinuses.The pathogenesis of thrombotic events in MPNs is complex and requires an intricate mechanism involving endothelial injury,stasis,elevated leukocyte adhesion,integrins,neutrophil extracellular traps,somatic mutations(e.g.,the V617F point mutation in the JAK2 gene),microparticles,circulating endothelial cells,and other factors,to name a few.Herein,we review the available data on Budd-Chiari syndrome in Philadelphia-negative MPNs,with a particular focus on its epidemiology,pathogenesis,histopathology,risk factors,classification,clinical presentation,diagnosis,and management.

Acute myocardial infarction in myeloproliferative neoplasms

Myeloproliferative neoplasms(MPNs)are a heterogeneous group of hematologic malignancies characterized by an abnormal proliferation of cells of the myeloid lineage.Affected individuals are at increased risk for cardiovascular and thrombotic events.Myocardial infarction(MI)may be one of the earliest clinical manifestations of MPNs or may be a thrombotic complication that develops during the natural course of the disease.In the present review,we examine the epidemiology,pathogenesis,clinical presentation,and management of MI in MPNs based on the available literature.Moreover,we review potential biomarkers that could mediate the MI-MPNs crosstalk,from classical biochemical tests,e.g.,lactate dehydrogenase,creatine kinase and troponins,to pro-inflammatory cytokines,oxidative stress markers,and clonal hematopoiesis.

Risk of hepatitis B reactivation in patients with myeloproliferative neoplasms treated with ruxolitinib

Classical Philadelphia-negative myeloproliferative neoplasms(MPNs),i.e.,polycythemia vera,essential thrombocythemia,and primary/secondary myelofibrosis,are clonal disorders of the hematopoietic stem cell in which an uncontrolled proliferation of terminally differentiated myeloid cells occurs.MPNs are characterized by mutations in driver genes,the JAK2V617F point mutation being the most commonly detected genetic alteration in these hematological malignancies.Thus,JAK inhibition has emerged as a potential therapeutic strategy in MPNs,with ruxolitinib being the first JAK inhibitor developed,approved,and prescribed in the management of these blood cancers.However,the use of ruxolitinib has been associated with a potential risk of infection,including opportunistic infections and reactivation of hepatitis B.Here,we briefly describe the association between ruxolitinib treatment in MPNs and hepatitis B reactivation.

Toxicity of targeted anticancer treatments on the liver in myeloproliferative neoplasms

The liver has a central role in metabolism,therefore,it is susceptible to harmful effects of ingested medications(drugs,herbs,and nutritional supplements).Druginduced liver injury(DILI)comprises a range of unexpected reactions that occur after exposure to various classes of medication.Even though most cases consist of mild,temporary elevations in liver enzyme markers,DILI can also manifest as acute liver failure in some patients and can be associated with mortality.Herein,we briefly review available data on DILI induced by targeted anticancer agents in managing classical myeloproliferative neoplasms:Chronic myeloid leukemia,polycythemia vera,essential thrombocythemia,and myelofibrosis.

Exploring the mechanism of action of DHI on myeloproliferative neoplasms based on network pharmacology

Objective:The aim of this study is to explore the active ingredients and mechanism of action of danhong injection(DHI)in treating myeloproliferative neoplasms using network pharmacology.Methods:The TCMSP platform and relevant literature were used to search for the active ingredients and targets of Radix Salviae and Carthami Flos in DHI.Disease targets related to myeloproliferative neoplasms were obtained from the GEO database,GeneCards,and DisGeNET database.The queried component targets were normalized using the UniProt database.Potential targets were identified by constructing protein-protein interactions networks using STRING 11.5 and visualized and analyzed using Cytoscape 3.9.1.GO and KEGG analysis were performed using the Metascape platform,and visualization was done using the built-in plug-in CluoGO or SangerBox platforms with Cytoscape 3.9.1.Results:The active ingredients of DHI for treating myeloproliferative neoplasms mainly consist of flavonoids and o-benzoquinones,including quercetin,luteolin,kaempferol,stigmasterol,tanshinone iia,cryptotanshinone,beta-carotene,2-isopropyl-8-methylphenanthrene-3,4-dione,and neocryptotanshinone ii.The potential targets are JUN,TP53,STAT3,AKT1,MAPK1,RELA,TNF,MAPK14,IL6,and FOS.The relevant signaling pathways involved are mainly TNFαsignaling pathway,PI3K-Akt signaling pathway,apoptosis,IL-17 signaling pathway,cellular senescence,MAPK signaling pathway,p53 signaling pathway,JAK-STAT signaling pathway,and NF-kappa B signaling.Conclusions:DHI acts mainly through flavonoids and o-benzoquinones to treat myeloproliferative neoplasms in a multi-targeted and multi-pathway manner.

Clinical management of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes

The myelodysplastic/myeloproliferative neoplasms(MDS/MPNs) are a unique group of hematologic malignancies characterized by concomitant myelodysplastic and myeloproliferative features. According to the 2008 WHO classification, the category includes atypical chronic myeloid leukemia(a CML), chronic myelomonocytic leukemia(CMML), juvenile myelomonocytic leukemia(JMML), MDS/MPN-unclassifiable(MDS/MPN-U), and the provisional entity refractory anemia with ring sideroblasts and thrombocytosis(RARS-T). Although diagnosis currently remains based on clinicopathologic features, the incorporation of nextgeneration platforms has allowed for the recent molecular characterization of these diseases which has revealed unique and complex mutational profiles that support their distinct biology and is anticipated to soon play an integral role in diagnosis,prognostication, and treatment. Future goals of research should include the development of disease-modifying therapies, and further genetic understanding of the category will likely form the foundation of these efforts.

Myeloproliferative neoplasms complicated withβ-thalassemia:Two case report

BACKGROUND BCR-ABL-negative myeloproliferative neoplasms(MPNs)are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages and by mutually exclusive JAK2 V617F,CALR,and MPL[A1]mutations.The combination of MPN and thalassemia is extremely unusual.Several cases with myeloproliferative neoplasms andβ-thalassemia have been reported.However,these have not been extensively reviewed.The present report describes two cases of myeloproliferative neoplasms complicated withβ-thalassemia and reviews all similar cases reported in the literature.CASE SUMMARY We report two patients who were diagnosed with myeloproliferative neoplasms complicated withβ-thalassemia.Both patients had abnormal increases in platelet counts.Based on bone marrow pathology and molecular biology assessment,we made the diagnosis of myeloproliferative neoplasms complicated withβ-thalassemia.The female patient was given hydroxyurea and interferon,which enabled good control of her blood counts;the male patient was given ruxolitinib tablets,thalidomide tablets,and interferon to control the condition,but the patient poorly responded to drug treatment and died of gastrointestinal bleeding six months later.CONCLUSION Given the findings of our cases and the literature review,we hypothesize that myeloproliferative neoplasms complicated withβ-thalassemia can lead to rapid disease progression and a poor prognosis.

Identification of <i>JAK2</i>(V617F) Mutation in Myeloproliferative Neoplasms by Using Allele Specific Polymerase Chain Reaction (AS-PCR)

Myeloproliferative neoplasms (MPNs) are a group of clonal haematopoietic stem cell disorders characterized by the proliferation of one or more myeloid cell lineages. According to WHO classification, the Janus associated kinase 2 (JAK2) V617F mutation is one of the major diagnostic criteria in BCR-ABL1 negative myeloproliferative neoplasms. The aim of this study is to detect the JAK2 (V617F) mutation in patients with myeloproliferative neoplasms to get accurate diagnosis and proper management. A total of 90 clinically diagnosed MPN patients attending to Department of Clinical Haematology, Yangon General Hospital were enrolled in this study. The mean age was 53.4 ± 14 years which ranged from 16 to 81 years old and male and female ratio was 2.4:1. The identification of JAK2 (V617F) point mutation was found to be positive in 44/90 MPN patients (48.9%). According to MPN subtypes, the JAK2 mutation positivity was found in 19 out of 46 polycythemia vera patients (41.3%), 17 out of 25 essential thrombocythemia patients (68%), 8 out of 15 primary myelofibrosis patients (53.3%), 0 of 4 others myeloproliferative neoplasms (0%). Confirmation of each of nine JAK2 mutation positive and negative samples was done by Sanger sequencing. The arterial or venous thrombotic attack was found in 32/44 JAK2 mutation positive cases (72.7%) and 12/44 JAK2 mutation negative cases (27.3%). The association between thrombotic attack and presence of JAK2 mutation was statistically significance with p = 0.000. The diagnosis of myeloproliferative neoplasms mainly relies on the molecular genetics according to WHO classification. The Allele specific PCR reaction is sensitive, simple test and relatively cost-effective. Therefore, the identification of JAK2 (V617F) somatic point mutation by AS-PCR should be implemented as a routine diagnosis procedure for patients with chronic and suspected myeloproliferative neoplasms.

Incidence in Ph-Negative Myeloproliferative Neoplasms in Armenia from 2005 to 2019

Introduction: Enhancements of laboratory diagnostics and the emergence of new therapies had a significant impact on the incidence, prevalence and survival of patients with myeloproliferative neoplasms (MPN). Published epidemiology data are scarce, and multiple sources are needed to assess the disease burden. The aim of our work was to identify the patterns and trends of incidence, prevalence and survival of patients with MPN in the Republic of Armenia (RA) for the period 2005-2019. Methods: The data from Hematology Center blood diseases register, Oncological Center cancer register, as well as the data from death registration were the basis of our research. Demographic data were obtained from National Statistical Office of RA. Results: Analysis of the data obtained has shown that during the reporting period the average annual incidence of MPN was 1.84 per 100.000 inhabitants, including 2.1 for males and 1.64 for females. Analysis of incidence rates of MPN in relation to sex and age in the period under study revealed high rates in patients in groups 65 - 74 (8.3) and 55 - 64 (5.12 per 100 thousand years), respectively. According to the data obtained in the group of patients with MPN, the high annual average incidence rates are noted in primary myelofibrosis (PMF) (1.09 in 2018) and polycythemia vera (PV) (0.89 in 2016), the lowest for essential thrombocythemia (ET) (0.7 in 2016) per 100.000 population, respectively. In comparing our data to those obtained for 1966-1971 and 1998-2004 periods, one may detect a statistically significant increase in the total incidence of PMF and PV (p < 0.001). Conclusions: Analysis of the incidence rate in MPNs adjusted for age and gender shown the prevalence in group 65 - 74 (8.3) and in group 55 - 64 (5.13) per 100,000 inhabitants. The peak of incidence rate for both males and females was the age 65 - 74 and the male female incidence ratio in this age group was 11.3:6.2. The increasing incidence rate in MPNs in Armenia depends on the improvement of laboratory diagnosis. Thrombotic complications are observed in patients with an MPN in 45.3% of cases. In most cases, thrombosis is the first clinical symptom of an MPN, which determines the need for the introduction into clinical practice of molecular genetic testing methods among patients with thrombosis, an increase in blood levels, splenomegaly for the early diagnosis of clonal hematopoiesis and the use of a targeted drug.

Network pharmacology prediction and molecular docking-based strategy to investigate the possibility of CPL against myeloproliferative neoplasms

Background:Compound cortex phellodendri liquid(CPL)is a kind of classical compound preparation,which has potential curative effect in treating inflammatory diseases.Increasing evidences support that inflammation plays important roles in the pathogenesis of myeloproliferative neoplasms(MPN).This study aims to preliminarily clarify the therapeutic potential and molecular mechanisms of CPL for MPN based on network pharmacology and molecular docking techniques.Methods:The active components and corresponding action targets of CPL were searched by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),while MPN-related targets were searched through GeneCards,DisGeNET,OMIM,DrugBank and TTD databases respectively.Protein-Protein Interaction(PPI)Networks of potential targets were constructed using STRING 11.5 and analyzed visually with Cytoscape 3.9.1.In addition,Metascape platform was used for GO and KEGG analysis that were subsequently visualized with Cytoscape 3.9.1 built-in plug-ins CluoGO or SangerBox platform.Finally,Autodock Vina was used for molecular docking of potential targets and main active ingredients,which were visualized with Pymol software.Experimentally,we used in vitro mouse primary cells culture system to evaluate the effect of CPL on the erythroid and megakaryocytes differentiation that are excessively driven in MPN respectively.Results:The active components of CPL in the treatment of MPN are mainly flavonoids.The core proteins of CPL for MPN intervention are correlated to TP53,AKT1,JUN,CASP3,EGFR,TNF,MYC,IL6.Multiple signaling pathways were closely related to the treatment of MPN intervened by CPL,including PI3K-Akt signaling,TNF-αsignaling,JAK-STAT signaling and NF-κB signaling pathways.These potential targets had good conformation with the core active ingredients of CPL.In line with above findings,we demonstrated that CPL significantly inhibits the proliferation of differentiation of erythrocytes and megakaryocytes in vitro,further supporting the therapeutic potential of CPL for MPN.Conclusion:This study revealed the active ingredients and potential molecular mechanism of CPL in the treatment of MPN,providing a reference for subsequent basic research.

Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins

Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms(MPNs);however,a considerable number of patients respond suboptimally.Here,we evaluated the efficacy of micheliolide(MCL),a natural guaianolide sesquiterpene lactone,alone or in combination with ruxolitinib in samples from patients with MPNs,JAK2V617F-mutated MPN cell lines,and a Jak2V617F knock-in mouse model.MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro.Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone.Moreover,dimethylaminomicheliolide(DMAMCL),an orally available derivative of MCL,significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis.Importantly,MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo.Mechanistically,MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation,thus inhibiting JAK/STAT signaling.Overall,these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.

Mutation profiles of classic myeloproliferative neoplasms detected by a customized next-generation sequencing-based 50-gene panel

Objective:A sequencing panel consisting of 50 genes was customized to reveal the potential molecular land-scapes of essential thrombocytosis,polycythemia vera,and primary myelofibrosis in Chinese patients with myeloproliferative neoplasm(MPN).Methods:Sixty-five MPN patients(38 with essential thrombocytosis,21 with polycythemia vera,and 6 with primary myelofibrosis),including 12 triple-negative patients,were recruited and were screened for their mutational spectrum using next-generation sequencing technology in this retrospective observational study.This study was approved by the Institutional Review Board of Changhai Hospital,Naval Military Medical University,China.Results:In addition to the typical driver mutations in JAK2,CALR,and MPL,pathogenic mutations in 15 other genes were frequently detected among the 65 patients with MPN.The 15 mutated genes were TET2,EZH2,ASXL1,MIR662,MLH1,MLH3,SF3B1,MSH6,BARD1,DNMT3A,KIT,MSH2,RUNX1,TP53,and NRAS in this order according to the mutational frequency detected.The average number of mutated genes was 1.2 genes per patient,while in the 12 triple-negative patients with MPN(ie,patients that lack the JAK2,CALR,or MPL mutations),at least one of the 15 pathogenic mutations was detected for each patient.Interestingly,4 single nucleotide polymorphisms(rs4858647,rs9376092,rs58270997,rs621940)that might be correlated to individual susceptibility to myeloproliferative neoplasm were identified among the 65 patients.We also found that single nucleotide polymorphism and/or single nucleotide variation mutations occurred in multiple loci of mismatch repair-related genes,which might contribute to the development of MPN.Conclusion:Our study confirms the importance of the previously known MPN relative genes and,more importantly,provides some new and potentially valuable information about mutations associated with MPNs.

Co-existing squamous cell carcinoma and chronic myelomonocytic leukemia with ASXL1 and EZH2 gene mutations:A case report

BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily progresses to acute myeloid leukemia.The simultaneous incidence of hematologic malignancies and solid tumors is extremely low,and CMML coinciding with lung malignancies is even rarer.Here,we report a case of CMML,with ASXL1 and EZH2 gene mutations,combined with non-small cell lung cancer(lung squamous cell carcinoma).CASE SUMMARY A 63-year-old male,suffering from toothache accompanied by coughing,sputum,and bloody sputum for three months,was given a blood test after experiencing continuous bleeding resulting from a tooth extraction at a local hospital.Based on morphological results,the patient was diagnosed with CMML and bronchoscopy was performed in situ to confirm the diagnosis of squamous cell carcinoma in the lower lobe of the lung.After receiving azacitidine,programmed cell death protein 1,and platinum-based chemotherapy drugs,the patient developed severe myelosuppression and eventually fatal leukocyte stasis and dyspnea.CONCLUSION During the treatment and observation of CMML and be vigilant of the growth of multiple primary malignant tumors.

MPN与CLL/SLL共患病的研究进展

骨髓增殖性肿瘤(myeloproliferative neoplasms,MPN)和慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(chronic lymphocytic leukemia/small lymphocytic lymphoma,CLL/SLL)是发病机制不同的两种血液系统肿瘤。两种疾病发生于同一患者非常罕见,目前全球仅报道了42例患者。其发生机制尚不清楚,两种肿瘤之间的相互关系也存在争论。临床特点上,当患者确诊时,CLL/SLL往往处于临床早期阶段;而且针对任何一种肿瘤的治疗均不会影响另一肿瘤的疾病进程;此外,同时患有这两种肿瘤不是预后不良的危险因素。本文就MPN和CLL/SLL共患病的研究进展进行综述。

Advances in the Study of High-Risk Gene Mutations for Primary Myelofibrosis

Primary myelofibrosis is a kind of MPNs due to clonal appreciation of hematopoietic stem cells. With the development of second-generation sequencing, high-risk mutation (HMR) genes such as ASXL1, EZH2, SRSF2, and IDH1/2 have been shown to be associated with disease prognosis and progression, and although allo-HSCT remains the only possible treatment for PMF, with the development of JAK inhibitors, there is an increasing interest in the study of inhibitors of these mutant loci.

IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia

The morbidity and mortality of myeloproliferative neoplasms(MPNs)are primarily caused by arterial and venous complications,progression to myelofibrosis,and transformation to acute leukemia.However,identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge.We have previously shown that interferon regulatory factor-8(IRF8)and IRF4 serve as tumor suppressors in myeloid cells.In this study,we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs.Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis(MF)and secondary AML(sAML)transformed from MPNs versus essential thrombocythemia(ET).Negative correlations between the JAK2V617F allele burden and the expression of IRF8(P<0.05)and IRF4(P<0.001)and between white blood cell(WBC)count and IRF4 expression(P<0.05)were found in ET patients.IRF8 expression was negatively correlated with the JAK2V617F allele burden(P<0.05)in polycythemia vera patients.Complete response(CR),partial response(PR),and no response(NR)were observed in 67.5%,10%,and 22.5%of ET patients treated with hydroxyurea(HU),respectively,in 12 months.At 3 months,patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups.In the 12-month therapy period,low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count.Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype,which may serve as biomarkers for the response to HU in ET.