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3.
Rinsho Ketsueki ; 65(5): 375-384, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38825516

RESUMO

Many novel agents have been developed for BCR::ABL1-negaive myeloproliferative neoplasms (MPN), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Some of these agents not only achieve hematologic complete response, reduce spleen size, and alleviate constitutional symptoms, but also induce molecular response, which means that they reduce the allele burden of driver gene mutations. These agents also prevent and alleviate fibrosis in bone marrow, which reduces the incidence of thrombotic events and disease progression and might improve prognosis. This article discusses the latest findings and promising treatments, including ongoing clinical trials, in PV, ET, and PMF.


Assuntos
Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/terapia , Transtornos Mieloproliferativos/diagnóstico , Mutação , Terapia de Alvo Molecular
4.
Medicine (Baltimore) ; 103(24): e38556, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875377

RESUMO

This study aimed to assess hematological diseases next-generation sequencing (NGS) panel enhances the diagnosis and classification of myeloid neoplasms (MN) using the 5th edition of the WHO Classification of Hematolymphoid Tumors (WHO-HAEM5) and the International Consensus Classification (ICC) of Myeloid Tumors. A cohort of 112 patients diagnosed with MN according to the revised fourth edition of the WHO classification (WHO-HAEM4R) underwent testing with a 141-gene NGS panel for hematological diseases. Ancillary studies were also conducted, including bone marrow cytomorphology and routine cytogenetics. The cases were then reclassified according to WHO-HAEM5 and ICC to assess the practical impact of these 2 classifications. The mutation detection rates were 93% for acute myeloid leukemia (AML), 89% for myelodysplastic syndrome (MDS), 94% for myeloproliferative neoplasm (MPN), and 100% for myelodysplasia/myeloproliferative neoplasm (MDS/MPN) (WHO-HAEM4R). NGS provided subclassified information for 26 and 29 patients with WHO-HAEM5 and ICC, respectively. In MPN, NGS confirmed diagnoses in 16 cases by detecting JAK2, MPL, or CALR mutations, whereas 13 "triple-negative" MPN cases revealed at least 1 mutation. NGS panel testing for hematological diseases improves the diagnosis and classification of MN. When diagnosed with ICC, NGS produces more classification subtype information than WHO-HAEM5.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/classificação , Adulto , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/classificação , Idoso de 80 Anos ou mais , Janus Quinase 2/genética , Organização Mundial da Saúde , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/diagnóstico , Receptores de Trombopoetina/genética , Calreticulina/genética , Adulto Jovem
6.
Front Immunol ; 15: 1384509, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846951

RESUMO

Introduction: The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works. Materials and methods: We present an extension of the Cancitis model, which describes the development of myeloproliferative neoplasms and their interactions with inflammation, that explicitly models progenitor cells and can account for treatment with ruxolitinib through effects on the malignant stem cell response to cytokine signalling and the death rate of malignant progenitor cells. The model has been fitted to individual patients' data for the JAK2 V617F variant allele frequency from the COMFORT-II and RESPONSE studies for patients who had substantial reductions (20 percentage points or 90% of the baseline value) in their JAK2 V617F variant allele frequency (n = 24 in total). Results: The model fits very well to the patient data with an average root mean square error of 0.0249 (2.49%) when allowing ruxolitinib treatment to affect both malignant stem and progenitor cells. This average root mean square error is much lower than if allowing ruxolitinib treatment to affect only malignant stem or only malignant progenitor cells (average root mean square errors of 0.138 (13.8%) and 0.0874 (8.74%), respectively). Discussion: Systematic simulation studies and fitting of the model to the patient data suggest that an initial reduction of the malignant cell burden followed by a monotonic increase can be recapitulated by the model assuming that ruxolitinib affects only the death rate of malignant progenitor cells. For patients exhibiting a long-term reduction of the malignant cells, the model predicts that ruxolitinib also affects stem cell parameters, such as the malignant stem cells' response to cytokine signalling.


Assuntos
Janus Quinase 2 , Transtornos Mieloproliferativos , Nitrilas , Pirazóis , Pirimidinas , Humanos , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Janus Quinase 2/genética , Janus Quinase 2/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Modelos Teóricos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia
8.
J Hematol Oncol ; 17(1): 43, 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853260

RESUMO

BACKGROUND: Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils. METHODS: Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1ß. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied. RESULTS: Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals. CONCLUSIONS: Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease.


Assuntos
Inflamação , Janus Quinase 2 , Transtornos Mieloproliferativos , Neutrófilos , Animais , Neutrófilos/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Camundongos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/metabolismo , Humanos , Inflamação/genética , Inflamação/patologia , Calreticulina/genética , Calreticulina/metabolismo , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Citocinas/metabolismo
9.
Leuk Res ; 142: 107518, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38744144

RESUMO

We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0-38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.


Assuntos
Azacitidina , Benzotiazóis , Mutação , Síndromes Mielodisplásicas , Compostos de Fenilureia , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Benzotiazóis/administração & dosagem , Benzotiazóis/uso terapêutico , Benzotiazóis/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas c-cbl/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Adulto
10.
Nature ; 629(8014): 1149-1157, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38720070

RESUMO

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.


Assuntos
Cromatina , Epigênese Genética , Genótipo , Mutação , Análise de Célula Única , Animais , Feminino , Humanos , Masculino , Camundongos , Antígenos CD34/metabolismo , Diferenciação Celular/genética , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética/genética , Epigenoma/genética , Genoma Mitocondrial/genética , Técnicas de Genotipagem , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Inflamação/genética , Inflamação/patologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Megacariócitos/metabolismo , Megacariócitos/patologia , Proteínas de Membrana/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , RNA/genética , Células Clonais/metabolismo
11.
Clin Exp Med ; 24(1): 106, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38771542

RESUMO

Typical BCR::ABL1-negative myeloproliferative neoplasms (MPN) are mainly referred to as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofbrosis (PMF). Granulocytes in MPN patients are involved in their inflammation and form an important part of the pathophysiology of MPN patients. It has been shown that the immunophenotype of granulocytes in MPN patients is altered. We used flow cytometry to explore the immunophenotype of MPN patients and correlate it with clinical parameters. The results showed that PMF patients and PV patients had higher CD15+CD11b+ granulocytes than ET patients and normal controls. When grouped by gene mutation, changes in the granulocyte immunophenotype of MPN patients were independent of the JAK2V617F and CALR mutations. There was no significant heterogeneity in immunophenotype between ET patients and Pre-PMF, and between Overt-PMF and Pre-PMF patients. Granulocytes from some MPN patients showed an abnormal CD13/CD16 phenotype with a significant increase in mature granulocytes on molecular and cytomorphological grounds, and this abnormal pattern occurred significantly more frequently in PMF patients than in ET patients. CD15-CD11b- was negatively correlated with WBC and Hb and positively correlated with DIPSS score, whereas high CD10+ granulocytes were significantly and negatively associated with prognostic system IPSS and DIPSS scores in PMF patients. In conclusion, this study demonstrates the landscape of bone marrow granulocyte immunophenotypes in MPN patients. MPN patients, especially those with PMF, have a significant granulocyte developmental overmaturation phenotype. CD10+ granulocytes may be involved in the prognosis of PMF patients.


Assuntos
Citometria de Fluxo , Proteínas de Fusão bcr-abl , Granulócitos , Imunofenotipagem , Transtornos Mieloproliferativos , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Granulócitos/patologia , Adulto , Idoso , Proteínas de Fusão bcr-abl/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia , Transtornos Mieloproliferativos/patologia , Janus Quinase 2/genética , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Idoso de 80 Anos ou mais , China , Adulto Jovem , Calreticulina/genética , Antígeno CD11b/genética , Policitemia Vera/genética , Policitemia Vera/patologia , Policitemia Vera/imunologia , Mutação , Povo Asiático/genética , População do Leste Asiático
12.
Clin Exp Med ; 24(1): 107, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38776019

RESUMO

Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events.


Assuntos
Proteínas de Fusão bcr-abl , Transtornos Mieloproliferativos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/diagnóstico , Proteínas de Fusão bcr-abl/genética , Trombomodulina/sangue , Fibrinolisina/metabolismo , Fibrinolisina/análise , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Antitrombina III/genética , Trombose , Hemorragia , Relevância Clínica , alfa 2-Antiplasmina , Peptídeo Hidrolases
14.
J Clin Neurosci ; 125: 159-166, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38815302

RESUMO

BACKGROUND: Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs) are linked with various complications, notably ischemic stroke. The study aims to identify risk factors for ischemic stroke in Ph-negative MPNs patients. METHODS: Patients were categorized into two groups based on whether they had experienced ischemic stroke. Subsequently, an analysis of demographics, biochemical makers, and genetic mutations (JAK2V617F and CALR mutations), was conducted to identify potential associations with an elevated risk of ischemic stroke in individuals with Ph-negative MPNs. RESULTS: A total of 185 patients diagnosed with Ph-negative MPNs participated in the study, including 82 with essential thrombocythemia (ET), 78 with polycythemia vera (PV), and 25 with primary myelofibrosis (PMF). Among these, 57 patients (30.8 %) had a history of ischemic stroke. Independent risk factors associated with ischemic stroke in Ph-negative MPNs patients included hypertension (OR = 5.076) and smoking (OR = 5.426). Among ET patients, smoking (OR = 4.114) and an elevated percentage of neutrophils (OR = 1.080) were both positively correlated with ischemic stroke incidence. For PV patients, hypertension (OR = 4.647), smoking (OR = 6.065), and an increased percentage of lymphocytes (OR = 1.039) were independently associated with ischemic stroke. Regardless of the presence of the JAK2V617F mutation, hypertension was the sole positively and independently associated risk factor for ischemic stroke. The odds ratios for patients with the JAK2V617F mutation was 3.103, while for those without the mutation, it was 11.25. CONCLUSIONS: Hypertension was a more substantial factor associated with an increased incidence of ischemic stroke in Ph-negative MPNs patients.


Assuntos
AVC Isquêmico , Janus Quinase 2 , Transtornos Mieloproliferativos , Cromossomo Filadélfia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , AVC Isquêmico/epidemiologia , AVC Isquêmico/genética , Idoso , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/epidemiologia , Adulto , Hipertensão/complicações , Hipertensão/epidemiologia , Mutação , Calreticulina/genética , Idoso de 80 Anos ou mais , Fumar/efeitos adversos , Fumar/epidemiologia
16.
Clin Lab Med ; 44(2): 339-353, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38821648

RESUMO

Despite the apparent complexity of the molecular genetic underpinnings of myeloid neoplasms, most myeloid mutational profiles can be understood within a simple framework. Somatic mutations accumulate in hematopoietic stem cells with aging and toxic insults, termed clonal hematopoiesis. These "old stem cells" mutations, predominantly in the epigenetic and RNA spliceosome pathways, act as "founding" driver mutations leading to a clonal myeloid neoplasm when sufficient in number and clone size. Subsequent mutations can create the genetic flavor of the myeloid neoplasm ("backseat" drivers) due to their enrichment in certain entities or act as progression events ("aggressive" drivers) during clonal evolution.


Assuntos
Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/metabolismo
17.
Cancer Discov ; 14(5): 701-703, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690601

RESUMO

SUMMARY: Dunbar, Bowman, and colleagues present here a novel genetic mouse model with inducible and reversible expression of the JAK2V617F mutation in the endogenous locus. Results from this study clearly demonstrate an absolute requirement for myeloproliferative neoplasm-initiating cells for this mutation in their survival and imply that more efficacious inhibitors could be curative for these patients even in the setting of additional cooperating mutations. See related article by Dunbar et al., p. 737 (8).


Assuntos
Janus Quinase 2 , Transtornos Mieloproliferativos , Janus Quinase 2/genética , Janus Quinase 2/antagonistas & inibidores , Animais , Camundongos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Humanos , Mutação , Modelos Animais de Doenças , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia
18.
Hematology ; 29(1): 2360246, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38804886

RESUMO

BACKGROUND: Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients' clinical manifestations and outcomes. METHODS: A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021. RESULTS: A total of 50 patients with CALR-positive MPN were reviewed with a median follow-up of three years (1-11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with CALR type 1, 21 (42%) patients with CALR type 2, and 5 (10%) patients with none Type 1, none Type 2 CALR mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 CALR and JAK2 mutations, and 1(2%) with CALR type 1 and MPL mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying CALR 1 mutations, and 1 (2%) patient progressed to AML with CALR 2 mutation. CONCLUSION: The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.


Assuntos
Calreticulina , Mutação , Transtornos Mieloproliferativos , Centros de Atenção Terciária , Humanos , Calreticulina/genética , Masculino , Feminino , Transtornos Mieloproliferativos/genética , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Catar/epidemiologia , Idoso
19.
Vet Clin Pathol ; 53(2): 196-201, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38641552

RESUMO

A 6-year-old spayed female Scottish Fold cat presented with lethargy and anorexia. A complete blood cell count indicated severe anemia and mild thrombocytopenia. Examination of peripheral blood smears revealed marked changes in the erythroid lineage, including the presence of basophilic stippling and Howell-Jolly bodies as well as an increase in nucleated erythrocytes, polychromatophils, ovalocytes, and schistocytes. Additionally, some erythrocytes contained a ring or figure-eight shaped structure known as a Cabot ring, which were especially observed in polychromatophilic erythrocytes. Hemolytic diseases (Mycoplasma infection and IMHA) were diagnostically excluded, and the cat was treated through prednisolone administration, whole blood transfusion, and administration of vitamins (K2 and B12); however, the anemia progressively worsened. Cabot rings were observed until Day 22 and subsequently disappeared as the number of nucleated RBCs increased, and the erythrocyte lineage shifted to immature population. On Day 42, peripheral blood examination revealed further left shifting and appearance of many rubriblasts. The patient died at home on Day 43. Necropsy revealed neoplastic cells infiltrating the bone marrow and other organs, which were immunopositive to CD71 which is an erythroid lineage marker. In humans, Cabot rings have been observed in megaloblastic anemia, lead poisoning, myelodysplastic syndrome, and myelofibrosis; further, they are thought to be related to stressed bone marrow and dyserythropoiesis. This is the first case report of a cat with Cabot rings, which are suggestive of defects in erythroid lineage production.


Assuntos
Doenças do Gato , Transtornos Mieloproliferativos , Gatos , Feminino , Doenças do Gato/patologia , Doenças do Gato/diagnóstico , Animais , Transtornos Mieloproliferativos/veterinária , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/complicações , Evolução Fatal , Eritrócitos Anormais/patologia , Anemia/veterinária , Anemia/patologia , Eritrócitos/patologia
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