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2.
Cell Rep ; 41(8): 111689, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36417879

RESUMO

Calreticulin (CALR) is an endoplasmic reticulum (ER)-retained chaperone that assists glycoproteins in obtaining their structure. CALR mutations occur in patients with myeloproliferative neoplasms (MPNs), and the ER retention of CALR mutants (CALR MUT) is reduced due to a lacking KDEL sequence. Here, we investigate the impact of CALR mutations on protein structure and protein levels in MPNs by subjecting primary patient samples and CALR-mutated cell lines to limited proteolysis-coupled mass spectrometry (LiP-MS). Especially glycoproteins are differentially expressed and undergo profound structural alterations in granulocytes and cell lines with homozygous, but not with heterozygous, CALR mutations. Furthermore, homozygous CALR mutations and loss of CALR equally perturb glycoprotein integrity, suggesting that loss-of-function attributes of mutated CALR chaperones (CALR MUT) lead to glycoprotein maturation defects. Finally, by investigating the misfolding of the CALR glycoprotein client myeloperoxidase (MPO), we provide molecular proof of protein misfolding in the presence of homozygous CALR mutations.


Assuntos
Calreticulina , Transtornos Mieloproliferativos , Humanos , Calreticulina/genética , Calreticulina/química , Calreticulina/metabolismo , Mutação/genética , Homozigoto , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteoma/metabolismo
3.
Best Pract Res Clin Haematol ; 35(2): 101374, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-36333071

RESUMO

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders commonly diagnosed in the seventh decade of life. With increasing access to blood surveillance, the number of adolescent and young adults (AYAs) diagnosed with MPNs is increasing. AYAs represent a unique cohort of MPN patients with differing challenges and psychosocial needs. The majority of AYA patients are females diagnosed with essential thrombocythaemia and most are asymptomatic at diagnosis. There is a striking predisposition to venous thrombotic events with a significant number experiencing splanchnic venous thrombosis (up to 70% of venous events). When compared to older patients, AYAs appear to have an indolent disease course. Interferon is the preferred cytoreductive agent in this population; indications for commencing treatment mirror those of older adults and are determined by the presence of high-risk features for thromboembolic events.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Trombocitemia Essencial , Trombose , Feminino , Humanos , Adulto Jovem , Adolescente , Idoso , Masculino , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/terapia , Trombocitemia Essencial/diagnóstico , Progressão da Doença
4.
Best Pract Res Clin Haematol ; 35(2): 101372, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-36333066

RESUMO

Patients with myeloproliferative neoplasms (MPNs) suffer from often debilitating constitutional symptoms that negatively impact quality of life to a degree similar to patients with metastatic solid tumors. Despite heterogeneity in the breadth and severity of symptoms in MPNs, research into symptom assessment has led to the creation of well validated patient reported outcome tools, including the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Currently available pharmacologic therapies, particularly JAK inhibitors, result in substantial reduction in symptom burden for patients with myelofibrosis, as well as select patient with polycythemia vera and essential thrombocythemia. Non-pharmacologic therapies including yoga and meditation have also been investigated. In this review, we focus on the pathogenesis and assessment of constitutional symptoms in MPNs. We detail currently available therapies to address symptom burden and highlight several novel agents in development. We end by discussing unmet needs and exploring the future of symptom assessment and treatment in MPNs.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Qualidade de Vida , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/terapia
5.
Best Pract Res Clin Haematol ; 35(2): 101379, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-36333070

RESUMO

Myeloproliferative neoplasms (MPN) have an inherent risk of transformation into blast phase (MPN-BP) or accelerated phase (MPN-AP) which is characterized by presence of ≥20% or 10-19% peripheral blood or bone marrow blasts, respectively. Primary myelofibrosis (PMF) is associated with the highest risk of blastic transformation (14.2%), followed by polycythemia vera (PV) (6.8%) and essential thrombocythemia (ET) (3.8%). Risk of leukaemic transformation (LT) in PMF can be determined by a three-tiered model based on presence of IDH1 mutation, circulating blasts ≥3%, SRSF2 mutation, age >70 years, ASXL1 mutation, and moderate/severe anemia with high, intermediate, and low risk groups (LT incidence 57%, 17%, and 8%, respectively). Currently, treatment of MPN-AP/BP includes acute myeloid leukaemia (AML)-like induction chemotherapy or hypomethylating agents alone or in combination with venetoclax and/or ruxolitinib. In transplant-eligible patients, our goal is to achieve complete remission with or without count recovery, before proceeding with allogeneic stem cell transplantation, which is the only modality associated with long-term survival. In the current review, we discuss our diagnostic, prognostic, and therapeutic approach to patients with MPN-AP/BP.


Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Idoso , Crise Blástica/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Prognóstico , Medula Óssea , Mutação
6.
Intern Med ; 61(22): 3323-3328, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36385045

RESUMO

Objective Thrombocytosis can occur as a primary event accompanying hematological diseases or as a secondary event. Since the publication of the World Health Organization classification in 2008, thrombocytosis is now generally defined as a platelet count above 450×109/L. Furthermore, the discovery of driver-gene mutations in myeloproliferative neoplasms (MPNs) has simplified the diagnostic approach for thrombocytosis. To identify the causes of thrombocytosis using this new definition, we conducted a retrospective study. Methods We identified outpatients and inpatients aged 20 years or older with platelet counts >450×109/L in a half-year period at a single institute and analyzed the causes of thrombocytosis and associated clinical characteristics. Results Among 1,202 patients with thrombocytosis, 150 (12.5%) had primary and 999 (83.1%) had secondary thrombocytosis. Of these patients with primary thrombocytosis, 129 (86%) had at least 1 molecular marker indicative of MPNs. The major causes of secondary thrombocytosis were tissue injury (32.2%), infection (17.1%), chronic inflammatory disorders (11.7%) and iron deficiency anemia (11.1%). The median platelet count and the incidence of thrombosis were significantly higher in patients with primary thrombocytosis than in those with secondary thrombocytosis. Conclusion Thrombocytosis mainly occurs as a secondary event; however, it is important to determine the cause of and prevent thrombosis, particularly in cases of primary thrombocytosis.


Assuntos
Transtornos Mieloproliferativos , Trombocitemia Essencial , Trombocitose , Trombose , Humanos , Estudos Retrospectivos , Trombocitemia Essencial/complicações , Trombocitemia Essencial/genética , Trombocitose/etiologia , Trombocitose/complicações , Contagem de Plaquetas , Transtornos Mieloproliferativos/complicações , Trombose/complicações
7.
J Investig Med High Impact Case Rep ; 10: 23247096221127114, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341907

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive malignancy with poor outcomes. Although novel options like tagraxofusp, a CD123-directed cytotoxin, has emerged and is promising, treatment options are very limited in the relapsed and recurrent setting. We present a case of refractory BPDCN in a 62-year-old man who showed a complete bone marrow response to liposomal daunorubicin and cytarabine (vyxeos).


Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Masculino , Humanos , Pessoa de Meia-Idade , Neoplasias Hematológicas/patologia , Citarabina , Células Dendríticas/patologia , Neoplasias Cutâneas/patologia , Daunorrubicina , Doença Aguda
8.
Expert Opin Pharmacother ; 23(17): 1915-1925, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36346029

RESUMO

INTRODUCTION: Pediatric acute myeloid leukemia (AML) is a rare disease that is profoundly heterogeneous at a molecular and clinical level. Although, in recent clinical trials, the 5-year event-free survival rates for childhood AML ranged between 49% and 64%, bone marrow relapse still occurs in up to one-third of cases. New therapies are required to continue progress in this aggressive hematological disease. Optimistically, we anticipate that the next challenge may be not a lack of appropriate therapies but an abundance of potentially effective strategies and a question of how best to incorporate them into pediatric clinical practice. AREAS COVERED: The focus of this review is to highlight all promising agents currently under investigation for pediatric AML, including nucleoside analogs, epigenetic modifiers, targeted small-molecule inhibitors, monoclonal antibodies, novel chemotherapeutics, and immunotherapies. EXPERT OPINION: While AML outcomes have improved over time for pediatric AML patients, our challenge is how to improve outcomes with our new knowledge of genetic and epigenetic aberrations. We posit to incorporate active therapy options into combination strategies and utilize targeted and immunotherapy approaches, as more opportunities are available.


Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Criança , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Imunoterapia , Anticorpos Monoclonais/uso terapêutico , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(5): 1627-1630, 2022 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-36208278

RESUMO

Classical myeloproliferative neoplasm (MPN) related thrombosis mainly affects elderly patients and often involves arterial circulation, while, MPN-visceral venous thrombosis (SVT) mainly affects young women, and is closely associated with JAK2V617F mutation but not closely with CALR mutation. The pathogenesis of MPN-SVT is not only related to JAK2V617F mutation and vascular endothelial damage, but also needs further research to determine the machanism. JAK2V617F mutation is the most common in MPN-SVT clinically. Patients with non-cirrhotic SVT need to detect MPN mutation, while the detection of CALR or MPL mutation needs to be combined with clinical judgment. At present, the main treatment strategies of MPN-SVT are JAK inhibitors, supplementation of anticoagulants and treatment of portal hypertension. This article reviews the latest research progress on the epidemiology, pathogenesis, diagnosis and treatment strategies of MPN-SVT.


Assuntos
Inibidores de Janus Quinases , Transtornos Mieloproliferativos , Neoplasias , Trombose , Trombose Venosa , Idoso , Anticoagulantes , Feminino , Humanos , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética
10.
Medicine (Baltimore) ; 101(38): e30622, 2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36197206

RESUMO

RATIONALE: Previous clinical reports of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) in pregnancy are rare. PATIENT CONCERNS: The present study presents the case of 37-year-old women exhibiting third trimester with progressive painless, abdominal skin nodules. INTERVENTIONS AND OUTCOMES: A 37-year-old pregnant woman with BPDCN and partial placenta previa and racket-shaped placenta. After comprehensive evaluation, the pregnancy status ends at 37 weeks and 6 days by cesarean section of lower uterus and no abnormality in the newborn. LESSONS: Pregnant women diagnosed with BPDCN in the third trimester should terminate the pregnancy promptly for further treatment.


Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Doença Aguda , Adulto , Cesárea , Células Dendríticas , Feminino , Neoplasias Hematológicas/terapia , Humanos , Recém-Nascido , Gravidez , Pele , Neoplasias Cutâneas/diagnóstico
12.
Front Immunol ; 13: 768592, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211444

RESUMO

In cancer, tumor cells and their neoplastic microenvironment can sculpt the immunogenic phenotype of a developing tumor. In this context, natural killer (NK) cells are subtypes of lymphocytes of the innate immune system recognized for their potential to eliminate neoplastic cells, not only through direct cytolytic activity but also by favoring the development of an adaptive antitumor immune response. Even though the protective effect against leukemia due to NK-cell alloreactivity mediated by the absence of the KIR-ligand has already been shown, and some data on the role of NK cells in myeloproliferative neoplasms (MPN) has been explored, their mechanisms of immune escape have not been fully investigated. It is still unclear whether NK cells can affect the biology of BCR-ABL1-negative MPN and which mechanisms are involved in the control of leukemic stem cell expansion. Aiming to investigate the potential contribution of NK cells to the pathogenesis of MPN, we characterized the frequency, receptor expression, maturation profile, and function of NK cells from a conditional Jak2V617F murine transgenic model, which faithfully resembles the main clinical and laboratory characteristics of human polycythemia vera, and MPN patients. Immunophenotypic analysis was performed to characterize NK frequency, their subtypes, and receptor expression in both mutated and wild-type samples. We observed a higher frequency of total NK cells in JAK2V617F mutated MPN and a maturation arrest that resulted in low-numbered mature CD11b+ NK cells and increased immature secretory CD27+ cells in both human and murine mutated samples. In agreement, inhibitory receptors were more expressed in MPN. NK cells from Jak2V617F mice presented a lower potential for proliferation and activation than wild-type NK cells. Colonies generated by murine hematopoietic stem cells (HSC) after mutated or wild-type NK co-culture exposure demonstrated that NK cells from Jak2V617F mice were deficient in regulating differentiation and clonogenic capacity. In conclusion, our findings suggest that NK cells have an immature profile with deficient cytotoxicity that may lead to impaired tumor surveillance in MPN. These data provide a new perspective on the behavior of NK cells in the context of myeloid malignancies and can contribute to the development of new therapeutic strategies, targeting onco-inflammatory pathways that can potentially control transformed HSCs.


Assuntos
Leucemia , Transtornos Mieloproliferativos , Animais , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Células Matadoras Naturais/metabolismo , Ligantes , Camundongos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Microambiente Tumoral/genética
14.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293440

RESUMO

Haplotype 46/1 (GGCC) consists of a set of genetic variations distributed along chromosome 9p.24.1, which extend from the Janus Kinase 2 gene to Insulin like 4. Marked by four jointly inherited variants (rs3780367, rs10974944, rs12343867, and rs1159782), this haplotype has a strong association with the development of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) because it precedes the acquisition of the JAK2V617F variant, a common genetic alteration in individuals with these hematological malignancies. It is also described as one of the factors that increases the risk of familial MPNs by more than five times, 46/1 is associated with events related to inflammatory dysregulation, splenomegaly, splanchnic vein thrombosis, Budd-Chiari syndrome, increases in RBC count, platelets, leukocytes, hematocrit, and hemoglobin, which are characteristic of MPNs, as well as other findings that are still being elucidated and which are of great interest for the etiopathological understanding of these hematological neoplasms. Considering these factors, the present review aims to describe the main findings and discussions involving the 46/1 haplotype, and highlights the molecular and immunological aspects and their relevance as a tool for clinical practice and investigation of familial cases.


Assuntos
Insulinas , Transtornos Mieloproliferativos , Neoplasias , Humanos , Janus Quinase 2/genética , Haplótipos , Transtornos Mieloproliferativos/genética , Suscetibilidade a Doenças , Insulinas/genética , Mutação
15.
Orv Hetil ; 163(44): 1758-1762, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36309891

RESUMO

Hypereosinophilic syndrome is characterized by chronic eosinophil overproduction, resulting in multiple organ damages due to eosinophil infiltration and mediator release. According to the etiology, we distinguish between myeloproliferative disorders, parasitic infections, solid tumors, T-cell lymphomas and idiopathic forms. In our case report, the 49-year-old man was hospitalized with weight loss, leg edema and tachycardia. In his laboratory tests increased biliary obstructive parameters as well as extreme leukocytosis and eosinophilia had been highlighted. We started our evaluation with a strong suspicion of hematologic malignancy. The CT scan of the thorax, abdomen and pelvis described hepatosplenomegaly, multiple intrahepatic lesions and an uncertain solitary cystic lesion in the tail of the pancreas with abnormal lymph nodes and pleural fluid. The described CT image and the other clinical parameters were primarily consistent with the manifestation of chronic myeloid leukemia. However, the diagnosis was not confirmed by peripheral blood smear, flow cytometry, bone marrow biopsy or genetic tests. After these results, we continued the assessment towards solid tumor associated leukemoid reaction, core biopsy was performed to verify the liver lesions. The biopsy confirmed the infiltration of a poorly differentiated epithelial tumor as a metastasis of pancreatobiliary carcinoma. To the best of our knowledge, this is the first case report on hypereosinophilic syndrome associated with gastrointestinal solid tumors in the Hungarian medical literature. It draws attention to the differential diagnosis of extreme leukocytosis and eosinophil ratios and by the absence of confirmed hematological disease the importance of early biopsy sampling of solid lesions. Orv Hetil. 2022; 163(44): 1758-1762.


Assuntos
Síndrome Hipereosinofílica , Transtornos Mieloproliferativos , Masculino , Humanos , Pessoa de Meia-Idade , Leucocitose/patologia , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/patologia , Medula Óssea/patologia , Eosinófilos
17.
Biomed Pharmacother ; 156: 113884, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36306591

RESUMO

Hyperactivation of the Janus kinase 2 (JAK2) signaling pathway leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 can be used as an effective strategy for the treatment of MPNs. Here, our study indicated that WWQ-131 was a highly selective JAK2 inhibitor (IC50 =2.36 nM), with 182-fold and 171-fold more selective to JAK1 and JAK3, respectively. In JAK2V617F-dependent cell lines, WWQ-131 efficaciously inhibited cell proliferation, induced cell cycle arrest at the G2/M phase and apoptosis, and blocked the aberrant activation of JAK2 signaling pathway. In a mouse Ba/F3_JAK2V617F driven disease model, WWQ-131 effectively suppressed STAT5 phosphorylation in spleen and liver, and inhibited Ba/F3_JAK2V617F cells spreading and proliferation in vivo. In addition, WWQ-131 suppressed rhEPO-induced extramedullary erythropoiesis and polycythemia in mice, as well as hematocrits and spleen sizes, especially had no effect on white blood cell count. Furthermore, WWQ-131 (75 mg/kg) exhibited stronger therapeutic effects than fedratinib (120 mg/kg) in these two MPN models. Taken together, this study suggests that WWQ-131 will be a promising candidate for the treatment of MPNs.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Camundongos , Animais , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/metabolismo , Proliferação de Células , Apoptose , Modelos Animais de Doenças , Mutação
18.
Exp Hematol ; 115: 14-19, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36183966

RESUMO

Next-generation sequencing technology, including whole-exome or whole-genome sequencing and target gene sequencing, has allowed the molecular characterization of somatic mutation spectrums in hematologic diseases. Mutations in Additional sex combs-like 1 (ASXL1), a chromatin regulator, are identified in clonal hematopoiesis of indeterminate potential (CHIP), indicating ASXL1 mutations as early events in leukemogenesis. Not surprisingly, they occur at high frequency in myeloid malignancies and are associated with poor prognosis. Therefore, understanding how mutant ASXL1 drives clonal expansion and leukemogenesis will serve as the basis for the future development of preventative and/or therapeutic strategies for myeloid diseases with ASXL1 mutations. Here, we discuss the biology of ASXL1 and its role in controlling normal and malignant hematopoiesis. In addition, we review the clinical relevance of ASXL1 mutations in CHIP and myeloid diseases.


Assuntos
Leucemia , Transtornos Mieloproliferativos , Humanos , Proteínas Repressoras/genética , Hematopoese/genética , Transtornos Mieloproliferativos/genética , Mutação , Leucemia/genética
19.
Ann Hematol ; 101(12): 2665-2677, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36266510

RESUMO

It has been postulated that the changes in the molecular characteristics of the malignant clone(s) and the abnormal activation of JAK-STAT signaling are responsible for myeloproliferative neoplasm progression to more advanced disease phases and the immune escape of the malignant clone. The continuous JAK-STAT pathway activation leads to enhanced activity of the promoter of CD274 coding programmed death-1 receptor ligand (PD-L1), increased PD-L1 level, and the immune escape of MPN cells. The aim of study was to evaluate the PDL1 mRNA and JAK2 mRNA level in molecularly defined essential thrombocythaemia (ET) patients (pts) during disease progression to post-ET- myelofibrosis (post-ET-MF). The study group consisted of 162 ET pts, including 30 pts diagnosed with post-ET-MF. The JAK2V617F, CALR, and MPL mutations were found in 59.3%, 19.1%, and 1.2% of pts, respectively. No copy-number alternations of the JAK2, PDL1, and PDCDL1G2 (PDL2) genes were found. The level of PD-L1 was significantly higher in the JAK2V617F than in the JAK2WT, CALR mutation-positive, and triple-negative pts. The PD-L1 mRNA level was weakly correlated with both the JAK2V617F variant allele frequency (VAF), and with the JAK2V617F allele mRNA level. The total JAK2 level in post-ET-MF pts was lower than in ET pts, despite the lack of differences in the JAK2V617F VAF. In addition, the PD-L1 level was lower in post-ET-MF. A detailed analysis has shown that the decrease in JAK2 and PDL1 mRNA levels depended on the bone marrow fibrosis grade. The PDL1 expression showed no differences in relation to the genotype of the JAK2 haplotypeGGCC_46/1, hemoglobin concentration, hematocrit value, leukocyte, and platelet counts. The observed drop of the total JAK2 and PDL1 levels during the ET progression to the post-ET-MF may reflect the changes in the JAK2V617F positive clone proliferative potential and the PD-L1 level-related immunosuppressive effect. The above-mentioned hypothesis is supported by The Cancer Genome Atlas (TCGA) data, confirming a strong positive association between CD274 (encoding PD-L1), CXCR3 (encoding CXCR3), and CSF1 (encoding M-CSF) expression levels, and recently published results documenting a drop in the CXCR3 level and circulating M-CSF in patients with post-ET-MF.


Assuntos
Transtornos Mieloproliferativos , Mielofibrose Primária , Trombocitemia Essencial , Humanos , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Mutação , RNA Mensageiro/genética , Calreticulina/genética , Calreticulina/metabolismo
20.
Ann Hematol ; 101(12): 2655-2663, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36269400

RESUMO

Molecular diagnostics moves more into focus as technology advances. In patients with myeloproliferative neoplasms (MPN), identification and monitoring of the driver mutations have become an integral part of diagnosis and monitoring of the disease. In some patients, none of the known driver mutations (JAK2V617F, CALR, MPL) is found, and they are termed "triple negative" (TN). Also, whole-blood variant allele frequency (VAF) of driver mutations may not adequately reflect the VAF in the stem cells driving the disease. We reasoned that colony forming unit (CFU) assay-derived clonogenic cells may be better suited than next-generation sequencing (NGS) of whole blood to detect driver mutations in TN patients and to provide a VAF of disease-driving cells. We have included 59 patients carrying the most common driver mutations in the establishment or our model. Interestingly, cloning efficiency correlated with whole blood VAF (p = 0.0048), suggesting that the number of disease-driving cells correlated with VAF. Furthermore, the clonogenic VAF correlated significantly with the NGS VAF (p < 0.0001). This correlation was lost in patients with an NGS VAF <15%. Further analysis showed that in patients with a VAF <15% by NGS, clonogenic VAF was higher than NGS VAF (p = 0.003), suggesting an enrichment of low numbers of disease-driving cells in CFU assays. However, our approach did not enhance the identification of driver mutations in 5 TN patients. A significant correlation of lactate dehydrogenase (LDH) serum levels with both CFU- and NGS-derived VAF was found. Our results demonstrate that enrichment for clonogenic cells can improve the detection of MPN driver mutations in patients with low VAF and that LDH levels correlate with VAF.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Calreticulina/genética , Calreticulina/metabolismo , Frequência do Gene , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética
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