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Scientific Reports Feb 2024Myeloproliferative neoplasms (MPNs) encompass a diverse group of hematologic disorders driven by mutations in JAK2, CALR, or MPL. The prevailing working model explaining...
Myeloproliferative neoplasms (MPNs) encompass a diverse group of hematologic disorders driven by mutations in JAK2, CALR, or MPL. The prevailing working model explaining how these driver mutations induce different disease phenotypes is based on the decisive influence of the cellular microenvironment and the acquisition of additional mutations. Here, we report increased levels of chromatin segregation errors in hematopoietic cells stably expressing CALRdel52 or JAK2V617F mutations. Our investigations employing murine 32D and human erythroleukemic TF-1 cells demonstrate a link between CALRdel52 or JAK2V617F expression and a compromised spindle assembly checkpoint (SAC), a phenomenon contributing to error-prone mitosis. This defective SAC is associated with imbalances in the recruitment of SAC factors to mitotic kinetochores upon CALRdel52 or JAK2V617F expression. We show that JAK2 mutant CD34 + MPN patient-derived cells exhibit reduced expression of the master mitotic regulators PLK1, aurora kinase B, and PP2A catalytic subunit. Furthermore, the expression profile of mitotic regulators in CD34 + patient-derived cells allows to faithfully distinguish patients from healthy controls, as well as to differentiate primary and secondary myelofibrosis from essential thrombocythemia and polycythemia vera. Altogether, our data suggest alterations in mitotic regulation as a potential driver in the pathogenesis in MPN.
Topics: Animals; Humans; Mice; Calreticulin; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Tumor Microenvironment
PubMed: 38308077
DOI: 10.1038/s41598-024-53240-8 -
Inflammation as a cause of acute myocardial infarction in patients with myeloproliferative neoplasm.World Journal of Cardiology Feb 2024Myeloproliferative neoplasms (MPN) are a group of diseases characterized by the clonal proliferation of hematopoietic progenitor or stem cells. They are clinically...
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.
PubMed: 38456066
DOI: 10.4330/wjc.v16.i2.58 -
Oncology Reports Jan 2024U2 small nuclear RNA auxiliary factor 1 (U2AF1) is a multifunctional protein that plays a crucial role in the regulation of RNA splicing during eukaryotic gene... (Review)
Review
U2 small nuclear RNA auxiliary factor 1 (U2AF1) is a multifunctional protein that plays a crucial role in the regulation of RNA splicing during eukaryotic gene expression. U2AF1 belongs to the SR family of splicing factors and is involved in the removal of introns from mRNAs and exon-exon binding. Mutations in U2AF1 are frequently observed in myelodysplastic syndrome, primary myelofibrosis, chronic myelomonocytic leukaemia, hairy cell leukaemia and other solid tumours, particularly in lung, pancreatic, and ovarian carcinomas. Therefore, targeting U2AF1 for therapeutic interventions may be a viable strategy for treating malignant diseases. In the present review, the pathogenic mechanisms associated with U2AF1 in different malignant diseases were summarized, and the potential of related targeting agents was discussed. Additionally, the feasibility of natural product-based therapies directed against U2AF1 was explored.
Topics: Humans; Splicing Factor U2AF; RNA Splicing Factors; Neoplasms; RNA Splicing; Mutation
PubMed: 37975232
DOI: 10.3892/or.2023.8664 -
Cureus Sep 2023Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder of the mature B-cells, mostly seen in men, and is characterized by cytopenia, splenomegaly,...
INTRODUCTION
Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder of the mature B-cells, mostly seen in men, and is characterized by cytopenia, splenomegaly, myelofibrosis, and the presence of atypical lymphoid cells showing the cytoplasmic hairy projection in the peripheral blood, bone marrow, and spleen. The immunophenotypic (IPT) profile shows the clonal expansion of B-cells with CD19, CD20, and CD22 showing bright expression. The diagnosis requires two hairy cell markers out of CD103, CD123, CD25, and CD11c to be positive. The HCL variant (HCL-v) has a different IPT profile with negative CD25 in most cases.
AIM
The aim was to study the hematological and IPT of classical HCL and HCL variants.
METHODS
This cross-sectional study included all the cases of HCL diagnosed over a retrospective period of eight years from 1st January 2015 to 31st December 2022 in a tertiary care hospital in north India. The patients included in the study were those for whom immunophenotyping; that is, flow cytometry and/or immunohistochemistry (IHC) were done for diagnosis. Bone marrow slides, IHC slides, and flow cytometric IPTs were reviewed.
RESULTS
The study included 13 patients who were diagnosed to have HCL, of which 12 were classical HCL and one was HCL-variant (HCL-v). Among classical HCL, IPT was done by flow cytometry in 10 patients, while in two patients, it was done by IHC. CD19, CD20, and CD22 were positive in all patients of classical HCL (10/10, 10/10, and 5/5, respectively), while CD123, CD103, CD25, and CD11C were positive in 100%, 89%, 80%, and 100% cases, respectively. One patient of HCL-v had CD103 and CD123 positive, while CD25 and CD123 were negative.
CONCLUSION
The diagnosis of HCL requires a multipronged approach. The use of clinical features, morphology, and immunophenotyping combined with ancillary techniques provides higher diagnostic accuracy and enables its distinction from other B-cell lymphoproliferative disorders (BCLPDs), leading to better patient management and treatment.
PubMed: 37814728
DOI: 10.7759/cureus.44876 -
Clinical Cancer Research : An Official... May 2024Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of...
PURPOSE
Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of Bcr-Abl-ve MPN, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF), and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear.
EXPERIMENTAL DESIGN
To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1,711 genes for mutations along with whole transcriptome RNA sequencing of 137 patients with MPN.
RESULTS
In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N = 106) and ET/PV/PrePMF (N = 31), respectively. Overt MF had more mutations compared with ET/PV/prePMF (5 vs. 4 per subject, P = 0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1) and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2, and NF1 were exclusive to MF. Advancing age, higher DIPSS, and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2, and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells.
CONCLUSIONS
Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression and potential targets for therapeutic intervention.
Topics: Humans; Primary Myelofibrosis; Mutation; Middle Aged; Aged; Male; Female; High-Throughput Nucleotide Sequencing; Adult; Aged, 80 and over; Genomics; Age Factors; Gene Expression Profiling; Transcriptome; Polycythemia Vera
PubMed: 38386293
DOI: 10.1158/1078-0432.CCR-23-0372 -
HemaSphere Nov 2023
PubMed: 37928624
DOI: 10.1097/HS9.0000000000000982 -
Haematologica Dec 2023The identification of patients at high risk of herpes zoster (HZ) requiring a prevention strategy with antiviral prophylaxis and anti-HZ vaccine is a clinically relevant...
Towards a personalized preventive strategy of Herpes zoster infection in patients with hematologic diseases or hematopoietic stem cell transplant recipients: a position paper from an Italian expert panel.
The identification of patients at high risk of herpes zoster (HZ) requiring a prevention strategy with antiviral prophylaxis and anti-HZ vaccine is a clinically relevant issue in patients with immunological impairment. Absence of trials comparing vaccination to pharmacological prophylaxis or defining their sequential use makes the optimal prevention strategy uncertain. This article presents the results of group discussion among an ad hoc constituted panel of experts aimed to review the literature regarding antiviral prophylaxis and vaccine efficacy and safety in populations with malignant and non-malignant hematological diseases, and submitted to hematopoietic stem cell transplantation. The panel used the consensus methodology and proposed solutions for prevention strategy producing advice for the management of the most relevant unmet clinical needs. Such a comprehensive overview aims to support at the practice of HZ pharmacological and vaccine prevention and informing the design and the need of implementation of new studies in the field.
PubMed: 38105723
DOI: 10.3324/haematol.2023.284417 -
American Journal of Hematology Mar 2024Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation in health and...
Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation in health and disease are still partially understood. We found PIEZO1, a mechanosensitive cation channel, to be expressed in mouse and human Mks. Human mutations in PIEZO1 have been described to be associated with blood cell disorders. Yet, a role for PIEZO1 in megakaryopoiesis and proplatelet formation has never been investigated. Here, we show that activation of PIEZO1 increases the number of immature Mks in mice, while the number of mature Mks and Mk ploidy level are reduced. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Similarly, in human samples, PIEZO1 is expressed during megakaryopoiesis. Its activation reduces Mk size, ploidy, maturation, and proplatelet extension. Resulting effects of PIEZO1 activation on Mks resemble the profile in Primary Myelofibrosis (PMF). Intriguingly, Mks derived from Jak2 PMF mice show significantly elevated PIEZO1 expression, compared to wild-type controls. Accordingly, Mks isolated from bone marrow aspirates of JAK2 PMF patients show increased PIEZO1 expression compared to Essential Thrombocythemia. Most importantly, PIEZO1 expression in bone marrow Mks is inversely correlated with patient platelet count. The ploidy, maturation, and proplatelet formation of Mks from JAK2 PMF patients are rescued upon PIEZO1 inhibition. Together, our data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation in PMF Mks might contribute to aggravating some hallmarks of the disease.
Topics: Humans; Animals; Mice; Megakaryocytes; Primary Myelofibrosis; Bone Marrow; Thrombopoiesis; Thrombocythemia, Essential; Blood Platelets; Ion Channels
PubMed: 38165047
DOI: 10.1002/ajh.27184 -
Cancers Oct 2023The aim of this study was to analyze the therapeutic results and survival of patients with myelofibrosis treated with ruxolitinib in comparison with a group on standard...
The aim of this study was to analyze the therapeutic results and survival of patients with myelofibrosis treated with ruxolitinib in comparison with a group on standard therapy. It is a cross-sectional, retrospective, non-interventional, real-life study that was performed between January 2000 and February 2023. Patients treated between 2000 and 2016, before the introduction of ruxolitinib, constituted the control group ( = 45), while those treated after May 2016, after ruxolitinib inclusion, constituted the active group ( = 66). Demographic characteristics, clinical indicators, the severity of the disease, and survival were explored using Kaplan-Meier survival analyses. Spearman's correlation, linear regression, and other statistical analyses were performed. According to the Kaplan-Meier analysis, there was a 75.33% reduction in the fatality risk in the sample. On a general-population level, the fatality risk in the group treated with ruxolitinib varied between 7.9% and 77.18% compared to that of the risk in the control group. There was a decrease in blood parameters (leukocytes, hemoglobin, and platelets) and spleen size. During the first six months, the spleen size of the patients on ruxolitinib decreased by 6%, and during the second six months, it decreased by another 9%. This study shows that patients in a real-life clinical setting treated with ruxolitinib exhibited improved clinical signs of the disease, had a lower symptom severity, and survived longer than patients on standard therapy before ruxolitinib's entrance into the national market. The improvements correlate with those reported in randomized clinical trials.
PubMed: 37894452
DOI: 10.3390/cancers15205085 -
Blood Advances Sep 2023Clinical implications of frailty in myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are...
Clinical implications of frailty in myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are unknown. In this population-based study, all incident cases of MPN from the Ontario cancer registry between 2004 and 2019 (N = 10 336; ET = 5108; PV = 3843; MF = 1385) and their matched controls (for age, sex, residence, and income) in a 1:4 ratio were included. Baseline frailty measured using the Johns Hopkins Adjusted Clinical Groups frailty indicator and McIsaac frailty index (mFI), categorized as fit, prefrail, or frail if mFI <0.10, 0.11 to 0.20, >0.20), was significantly higher in ET, PV, and MF compared with matched controls (standardized mean difference of 0.27, 0.27, and 0.28). Over 23%, 20%, and 34% of patients with ET, PV, and MF were frail or prefrail despite a younger age (<65 years) or minimal comorbidities. In Cox proportional regression, frailty was independently associated with worse overall survival (OS) after adjusting for age, sex, and comorbidities compared with mFI-fit patients. The hazard ratios (95% confidence interval) for OS for mFI-prefrail and mFI-frail patients were: 1.6 (1.3-1.9) and 3.6 (2.9-4.4) in ET, 1.3 (1.1-1.5) and 2.7 (2.1-3.4) in PV, and 1.2 (1.0-1.5) and 2.0 (1.5-2.7) in MF. Patients with MPN have a substantially higher prevalence of frailty compared with matched controls, which is associated with reduced OS, independent of age or comorbidities.
Topics: Humans; Aged; Prevalence; Frailty; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 37184988
DOI: 10.1182/bloodadvances.2023009825