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Clinical and Experimental Medicine Jan 2024Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no...
Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
Topics: Humans; Polycythemia; Polycythemia Vera; Mutation; Iron; Germ Cells
PubMed: 38244120
DOI: 10.1007/s10238-023-01283-y -
Blood Advances Nov 2023Red blood cells (RBCs) and platelets contribute to the coagulation capacity in bleeding and thrombotic disorders. The thrombin generation (TG) process is considered to...
Red blood cells (RBCs) and platelets contribute to the coagulation capacity in bleeding and thrombotic disorders. The thrombin generation (TG) process is considered to reflect the interactions between plasma coagulation and the various blood cells. Using a new high-throughput method capturing the complete TG curve, we were able to compare TG in whole blood and autologous platelet-rich and platelet-poor plasma to redefine the blood cell contributions to the clotting process. We report a faster and initially higher generation of thrombin and shorter coagulation time in whole blood than in platelet-rich plasma upon low concentrations of coagulant triggers, including tissue factor, Russell viper venom factor X, factor Xa, factor XIa, and thrombin. The TG was accelerated with increased hematocrit and delayed after prior treatment of RBC with phosphatidylserine-blocking annexin A5. RBC treatment with ionomycin increased phosphatidylserine exposure, confirmed by flow cytometry, and increased the TG process. In reconstituted blood samples, the prior selective blockage of phosphatidylserine on RBC with annexin A5 enhanced glycoprotein VI-induced platelet procoagulant activity. For patients with anemia or erythrocytosis, cluster analysis revealed high or low whole-blood TG profiles in specific cases of anemia. The TG profiles lowered upon annexin A5 addition in the presence of RBCs and thus were determined by the extent of phosphatidylserine exposure of blood cells. Profiles for patients with polycythemia vera undergoing treatment were similar to that of control subjects. We concluded that RBC and platelets, in a phosphatidylserine-dependent way, contribute to the TG process. Determination of the whole-blood hypo- or hyper-coagulant activity may help to characterize a bleeding or thrombosis risk.
Topics: Humans; Thrombin; Phosphatidylserines; Annexin A5; Erythrocytes; Thrombosis; Coagulants; Anemia
PubMed: 37648671
DOI: 10.1182/bloodadvances.2023010027 -
The Korean Journal of Internal Medicine Nov 2023Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells. The malignant clones produce cytokines that drive self-perpetuating inflammatory... (Review)
Review
Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells. The malignant clones produce cytokines that drive self-perpetuating inflammatory responses and tend to transform into more aggressive clones, leading to disease progression. The progression of MPNs follows a biological sequence from the early phases of malignancy, polycythemia vera, and essential thrombocythemia, to advanced myelofibrosis and leukemic transformation. To date, the treatment of MPNs has focused on preventing thrombosis by decreasing blood cell counts and relieving disease-related symptoms. However, interferon (IFN) has been used to treat MPNs because of its ability to attack cancer cells directly and modulate the immune system. IFN also has the potential to modulate diseases by inhibiting JAK2 mutations, and recent studies have demonstrated clinical and molecular improvements. Long-acting IFN is administered less frequently and has fewer adverse effects than conventional IFN. The current state of research on long-acting IFN in patients with MPNs is discussed, along with future directions.
Topics: Humans; Interferons; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Neoplasms; Mutation; Janus Kinase 2
PubMed: 37939664
DOI: 10.3904/kjim.2023.333 -
EJHaem Aug 2023Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare -negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic... (Review)
Review
Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare -negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.
PubMed: 37601853
DOI: 10.1002/jha2.734 -
Nature Communications May 2024Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we...
Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2 mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.
Topics: Polycythemia; Erythroblasts; Erythropoiesis; Heme; Humans; Animals; Lipoproteins; Macrophages; Mice; GATA1 Transcription Factor; Janus Kinase 2; Thrombomodulin; Mice, Knockout; Ferrochelatase; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Female
PubMed: 38729948
DOI: 10.1038/s41467-024-48328-8 -
Blood Jun 2023Polycythemia vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients'...
Polycythemia vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
Topics: Animals; Mice; Polycythemia Vera; Hepcidins; Genome-Wide Association Study; Iron; Phenotype; Homeostasis
PubMed: 36928379
DOI: 10.1182/blood.2022016779 -
Frontiers in Genetics 2023The classical -negative myeloproliferative neoplasms such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal diseases with the... (Review)
Review
The classical -negative myeloproliferative neoplasms such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal diseases with the presence of characteristic "driver mutations" in one of the genes: JAK2, CALR, or MPL. The search for mutations in these three genes is required for the diagnosis of MPNs. Nevertheless, the progress that has been made in the field of molecular genetics has opened a new era in medicine. The search for additional mutations in MPNs is helpful in assessing the risk stratification, disease progression, transformation to acute myeloid leukemia (AML), or choosing the right treatment. In some cases, advanced technologies are needed to find a clonal marker of the disease and establish a diagnosis. This review focuses on how the use of new technologies like next-generation sequencing (NGS) helps in the diagnosis of -negative myeloproliferative neoplasms.
PubMed: 37745842
DOI: 10.3389/fgene.2023.1241912 -
Blood Cancer Journal Nov 2023SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2...
SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2 mutation in JAK2V617F-driven MPN remains elusive. To investigate the consequences of SRSF2 and JAK2 mutations in MPN, we generated Cre-inducible Srsf2Jak2 knock-in mice. We show that co-expression of Srsf2 mutant reduced red blood cell, neutrophil, and platelet counts, attenuated splenomegaly but did not induce bone marrow fibrosis in Jak2 mice. Furthermore, co-expression of Srsf2 diminished the competitiveness of Jak2 mutant hematopoietic stem/progenitor cells. We found that Srsf2 mutant reduced the TGF-β levels but increased the expression of S100A8 and S100A9 in Jak2 mice. Furthermore, enforced expression of S100A9 in Jak2 mice bone marrow significantly reduced the red blood cell, hemoglobin, and hematocrit levels. Overall, these data suggest that concurrent expression of Srsf2 and Jak2 mutants reduces erythropoiesis but does not promote the development of bone marrow fibrosis in mice.
Topics: Animals; Mice; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Neoplasms; Polycythemia; Primary Myelofibrosis; Serine-Arginine Splicing Factors
PubMed: 38012156
DOI: 10.1038/s41408-023-00947-y -
JAMA Network Open Sep 2023Testosterone treatment is a necessary component of care for some transgender and gender-diverse individuals. Observational studies have reported associations between... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Testosterone treatment is a necessary component of care for some transgender and gender-diverse individuals. Observational studies have reported associations between commencement of gender-affirming hormone therapy and improvements in gender dysphoria and depression, but there is a lack of data from randomized clinical trials.
OBJECTIVE
To assess the effect of testosterone therapy compared with no treatment on gender dysphoria, depression, and suicidality in transgender and gender-diverse adults seeking masculinization.
DESIGN, SETTING, AND PARTICIPANTS
A 3-month open-label randomized clinical trial was conducted at endocrinology outpatient clinics and primary care clinics specializing in transgender and gender-diverse health in Melbourne, Australia, from November 1, 2021, to July 22, 2022. Participants included transgender and gender-diverse adults aged 18 to 70 years seeking initiation of testosterone therapy.
INTERVENTIONS
Immediate initiation of testosterone commencement (intervention group) or no treatment (standard care waiting list of 3 months before commencement). This design ensured no individuals would be waiting longer than the time to standard care.
MAIN OUTCOMES AND MEASURES
The primary outcome was gender dysphoria, as measured by the Gender Preoccupation and Stability Questionnaire. Secondary outcomes included the Patient Health Questionnaire-9 (PHQ-9) to assess depression and the Suicidal Ideation Attributes Scale (SIDAS) to assess suicidality. Questionnaires were undertaken at 0 and 3 months. The evaluable cohort was analyzed.
RESULTS
Sixty-four transgender and gender-diverse adults (median [IQR] age, 22.5 [20-27] years) were randomized. Compared with standard care, the intervention group had a decrease in gender dysphoria (mean difference, -7.2 points; 95% CI, -8.3 to -6.1 points; P < .001), a clinically significant decrease in depression (ie, change in score of 5 points on PHQ-9; mean difference, -5.6 points; 95% CI, -6.8 to -4.4 points; P < .001), and a significant decrease in suicidality (mean difference in SIDAS score, -6.5 points; 95% CI, -8.2 to -4.8 points; P < .001). Resolution of suicidality assessed by PHQ-9 item 9 occurred in 11 individuals (52%) with immediate testosterone commencement compared with 1 (5%) receiving standard care (P = .002). Seven individuals reported injection site pain/discomfort and 1 individual reported a transient headache 24 hours following intramuscular administration of testosterone undecanoate. No individual developed polycythemia.
CONCLUSIONS AND RELEVANCE
In this open-label randomized clinical trial of testosterone therapy in transgender and gender-diverse adults, immediate testosterone compared with no treatment significantly reduced gender dysphoria, depression, and suicidality in transgender and gender-diverse individuals desiring testosterone therapy.
TRIAL REGISTRATION
ANZCTR Identifier: ACTRN1262100016864.
Topics: Adult; Humans; Young Adult; Transgender Persons; Testosterone; Testosterone Congeners; Ambulatory Care Facilities; Australia
PubMed: 37676662
DOI: 10.1001/jamanetworkopen.2023.31919