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1.
Nat Commun ; 11(1): 4886, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985500

RESUMO

Somatic mutations in the calreticulin (CALR) gene are associated with approximately 30% of essential thrombocythemia (ET) and primary myelofibrosis (PMF). CALR mutations, including the two most frequent 52 bp deletion (del52) and 5 bp insertion (ins5), induce a frameshift to the same alternative reading frame generating new C-terminal tails. In patients, del52 and ins5 induce two phenotypically distinct myeloproliferative neoplasms (MPNs). They are equally found in ET, but del52 is more frequent in PMF. We generated heterozygous and homozygous conditional inducible knock-in (KI) mice expressing a chimeric murine CALR del52 or ins5 with the human mutated C-terminal tail to investigate their pathogenic effects on hematopoiesis. Del52 induces greater phenotypic changes than ins5 including thrombocytosis, leukocytosis, splenomegaly, bone marrow hypocellularity, megakaryocytic lineage amplification, expansion and competitive advantage of the hematopoietic stem cell compartment. Homozygosity amplifies these features, suggesting a distinct contribution of homozygous clones to human MPNs. Moreover, homozygous del52 KI mice display features of a penetrant myelofibrosis-like disorder with extramedullary hematopoiesis linked to splenomegaly, megakaryocyte hyperplasia and the presence of reticulin fibers. Overall, modeling del52 and ins5 mutations in mice successfully recapitulates the differences in phenotypes observed in patients.


Assuntos
Calreticulina/genética , Mielofibrose Primária/genética , Trombocitemia Essencial/genética , Animais , Calreticulina/metabolismo , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/metabolismo , Homozigoto , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese Insercional , Fenótipo , Mielofibrose Primária/metabolismo , Deleção de Sequência , Trombocitemia Essencial/metabolismo
2.
Medicine (Baltimore) ; 99(34): e21757, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846801

RESUMO

RATIONALE: Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition, which mainly manifests as headaches, seizures, and focal neurological deficits. JAK2 mutation in myeloproliferative diseases increases the risk of CVT. PATIENT CONCERNS: This 40-year-old woman suffered from rapidly progressive cognitive impairment and limb weakness. Her symptoms worsened while being treated with mannitol with the diagnose of cerebral hemorrhage. DIAGNOSIS: The patient was diagnosed with CVT and multiple intracranial hemorrhage caused by JAK2 V617F mutation-positive primary myelofibrosis by neuroimage and whole-exome sequencing. INTERVENTION: She received low-molecular-weight heparin sodium 3800 IU twice a day followed by oral anticoagulant therapy. OUTCOMES: The patient showed full recovery from limb weakness and in the follow-up period she noticed no change in her memory. LESSONS: Clinicians should be aware of the possibility of the JAK2 V617F mutation in CVT patients without known causes or risk factors.


Assuntos
Disfunção Cognitiva/etiologia , Trombose Intracraniana/etiologia , Janus Quinase 2/genética , Mielofibrose Primária/complicações , Trombose Venosa/etiologia , Adulto , Anticoagulantes/uso terapêutico , Feminino , Humanos , Trombose Intracraniana/tratamento farmacológico , Mielofibrose Primária/genética , Trombose Venosa/tratamento farmacológico
3.
PLoS One ; 15(6): e0232801, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479500

RESUMO

The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis are hematopoietic stem cell disorders and share driver mutations that either directly activate the thrombopoietin receptor, MPL, or activate it indirectly through gain-of-function mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, MPL surface expression in hematopoietic stem cells is also reduced in the myeloproliferative neoplasms due to abnormal post-translational glycosylation and premature destruction of JAK2, suggesting that the myeloproliferative neoplasms are disorders of MPL processing since MPL is the only hematopoietic growth factor receptor in hematopoietic stem cells. To examine this possibility, we genetically manipulated MPL expression and maturation in a JAK2V617F transgenic mouse model of polycythemia vera. Elimination of MPL expression completely abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could only be partially restored by expression of one MPL allele. Most importantly, elimination of thrombopoietin gene expression abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could be completely restored by expression of a single thrombopoietin allele. These data indicate that polycythemia vera is in part a thrombopoietin-dependent disorder and that targeting the MPL-thrombopoietin axis could be an effective, nonmyelotoxic therapeutic strategy in this disorder.


Assuntos
Janus Quinase 2/genética , Policitemia Vera/genética , Policitemia Vera/metabolismo , Trombopoetina/genética , Trombopoetina/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Transtornos Mieloproliferativos/genética , Fenótipo , Policitemia Vera/patologia , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética
4.
Ann Hematol ; 99(5): 983-989, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32277273

RESUMO

Molecular detection of JAK2 mutation (V617F or exon 12) is included as a major diagnostic criterion for polycythemia vera (PV) by the WHO 2016 guidelines. JAK2 exon 12 mutations are seen in about 2-5% of JAK2V617F-negative cases of PV. Mutations in JAK2 cause constitutive activation of JAK-STAT pathway which results in variable phenotypes. PV patients with exon 12 mutations in JAK2 present characteristically with erythrocytosis. There are limited reports describing the spectrum of JAK2 exon12 mutations in myeloproliferative neoplasms (MPNs). Here, we describe the characteristics of a series of MPN patients with mutations in exon 12 of JAK2 of which two were novel variants associated with polycythemia. Interestingly, we noted two patients presenting as myelofibrosis having JAK2 exon 12 mutations.


Assuntos
Éxons , Janus Quinase 2/genética , Mutação de Sentido Incorreto , Policitemia Vera/genética , Mielofibrose Primária/genética , Adulto , Substituição de Aminoácidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Pediatr Blood Cancer ; 67(5): e28232, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134181

RESUMO

OBJECTIVES: Pediatric myelofibrosis is a rare entity with the largest reported series of 19 cases. We describe here the clinicopathological spectrum and outcomes of 15 cases of pediatric myelofibrosis. METHODS: Case files of myelofibrosis of patients less than 18 years were retrieved from January 2016 to January 2019, and patients with idiopathic myelofibrosis after exhaustive work-up were studied. Their clinicopathological profiles were studied and then followed up for resolution and malignant transformation. RESULTS: Of the 15 cases of idiopathic myelofibrosis, transfusion-dependent anemia (14/15) was most common presentation. Only one patient showed leukoerythroblastosis with dacryocytes. Myeloid hyperplasia was seen in 13 of 15 patients and megakaryocytic hyperplasia in 10 patients. Dysmegakaryopoiesis was seen in 8 of 15 patients, and only three had small loose megakaryocytic clustering. None showed hyperchromatic megakaryocytes, intrasinusoidal hematopoiesis, or osteosclerosis. One patient with trisomy 8 tested positive for JAK2V617F. Bone marrow biopsy was hypercellular in 13, and 8 had world health organization (WHO) MF-3 fibrosis. None of the patients developed malignancy, one had spontaneous resolution, and one patient required allogenic stem cell transplant. CONCLUSIONS: Pediatric myelofibrosis is a distinct entity from primary myelofibrosis in adults and merits mention in the WHO manual as a distinct entity.


Assuntos
Transformação Celular Neoplásica , Janus Quinase 2 , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Trombopoese , Adolescente , Adulto , Substituição de Aminoácidos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Megacariócitos/metabolismo , Megacariócitos/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Estudos Retrospectivos
6.
Cytogenet Genome Res ; 160(1): 18-21, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32008001

RESUMO

Multiple isodicentric Y chromosomes [idic(Y)] is a rare cytogenetic abnormality, most exclusively described in constitutional karyotypes. Only recently has this entity been reported in hematologic neoplasms such as myeloid disorders, albeit these cases remain very scarce. The possible involvement of increasing copies of potential proto-oncogenes located on the multiple idic(Y) led to consider one of them, CRLF2, as a target for kinase inhibitors. We report here, to our knowledge, the first case of multiple idic(Y) in a patient with myelofibrosis secondary to essential thrombocythemia. The patient received ruxolitinib therapy with initial good clinical response.


Assuntos
Cromossomos Humanos Y/genética , Mielofibrose Primária/complicações , Aberrações dos Cromossomos Sexuais , Trombocitemia Essencial/complicações , Idoso , Alelos , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Cariotipagem , Masculino , Mosaicismo , Contagem de Plaquetas , Mielofibrose Primária/genética , Prognóstico , Pirazóis/uso terapêutico , Receptores de Citocinas/genética , Trombocitemia Essencial/genética
8.
Nat Commun ; 11(1): 73, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911629

RESUMO

Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.


Assuntos
Evolução Clonal , Mielofibrose Primária/genética , Idoso , Exoma , Feminino , Seguimentos , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteína Oncogênica p21(ras)/genética , Estudos Prospectivos , Análise de Célula Única , Células-Tronco/citologia
10.
Zhonghua Nei Ke Za Zhi ; 59(1): 35-39, 2020 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-31887834

RESUMO

Objective: To explore the relationship between driver gene mutation (JAK2, MPL and CALR) and disease type in BCR-ABL negative myeloproliferative neoplasms (MPNs) including primary myeloid fibrosis (PMF), essential thrombocytosis (ET) and polycythemia vera (PV). Methods: A total of 32 MPN related genes were detected by high-throughput sequencing in 156 MPN patients. The relationships between disease type and patients' general performance, the characteristics of driver gene mutations, concomitant gene mutations were analyzed. Results: In the population with JAK2 V617F positive mutation, the proportion of patients over 60 years old in PMF was higher than that with ET or PV. By high-throughput sequencing, 22 concomitant gene mutations were detected in 46 patients with JAK2, MPL or CALR mutations, including 4 (8.3%) in PV, 20 (29.4%) in ET, and 22 (55.0%) in PMF. DNMT3A mutation was detected only in patients with PV, while splicing factor related genes including SF3B1, SRSF2 and U2AF1 were only accompanied by PMF. According to the variation allele frequency (VAF) value of JAK2 V617F mutation, the VAF value associated with PV was the highest (68.15%), followed by PMF (37.7%) and ET (23%). However, there were significant differences in the incidence of JAK2 V617F homozygous among 3 different diseases. In patients with JAK2 mutation, the proportion of other gene mutations in PV and ET was significantly lower than that in PMF. Conclusions: Under the condition of common driver gene mutations (JAK2, MPL and CALR), patients' age, VAF value and homozygous state, concomitant gene mutations are closely related to different disease type. These correlations help to improve clinical understanding of disease characteristics and risk assessment.


Assuntos
Calreticulina/genética , Proteínas de Fusão bcr-abl/genética , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Receptores de Trombopoetina/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Calreticulina/metabolismo , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/metabolismo , Policitemia Vera/genética , Mielofibrose Primária/genética , Receptores de Trombopoetina/metabolismo , Trombocitemia Essencial/genética
11.
IUBMB Life ; 72(1): 131-141, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31749302

RESUMO

In 2002, we discovered that mice carrying the hypomorphic Gata1low mutation that reduces expression of the transcription factor GATA1 in megakaryocytes (Gata1low mice) develop myelofibrosis, a phenotype that recapitulates the features of primary myelofibrosis (PMF), the most severe of the Philadelphia-negative myeloproliferative neoplasms (MPNs). At that time, this discovery had a great impact on the field because mutations driving the development of PMF had yet to be discovered. Later studies identified that PMF, as the others MPNs, is associated with mutations activating the thrombopoietin/JAK2 axis raising great hope that JAK inhibitors may be effective to treat the disease. Unfortunately, ruxolitinib, the JAK1/2 inhibitor approved by FDA and EMEA for PMF, ameliorates symptoms but does not improve the natural course of the disease, and the cure of PMF is still an unmet clinical need. Although GATA1 is not mutated in PMF, reduced GATA1 content in megakaryocytes as a consequence of ribosomal deficiency is a hallmark of myelofibrosis (both in humans and mouse models) and, in fact, a driving event in the disease. Conversely, mice carrying the hypomorphic Gata1low mutation express an activated TPO/JAK2 pathway and partially respond to JAK inhibitors in a fashion similar to PMF patients (reduction of spleen size but limited improvement of the natural history of the disease). These observations cross-validated Gata1low mice as a bona fide animal model for PMF and prompted the use of this model to identify abnormalities that might be targeted to cure the disease. We will summarize here data generated in Gata1low mice indicating that the TGF-ß/P-selectin axis is abnormal in PMF and represents a novel target for its treatment.


Assuntos
Modelos Animais de Doenças , Fator de Transcrição GATA1/fisiologia , Megacariócitos/patologia , Mielofibrose Primária/terapia , Animais , Humanos , Megacariócitos/metabolismo , Camundongos , Camundongos Knockout , Mielofibrose Primária/genética , Mielofibrose Primária/patologia
12.
Nat Commun ; 10(1): 5386, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772163

RESUMO

Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS.


Assuntos
Mutação , Síndromes Mielodisplásicas/etiologia , Idoso , Feminino , Hematopoese/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Fenótipo , Fosfoproteínas/genética , Mielofibrose Primária/genética , Fatores de Processamento de RNA/genética , Fator de Processamento U2AF/genética , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Exoma
13.
Anticancer Res ; 39(11): 6273-6282, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704857

RESUMO

BACKGROUND/AIM: We have yet to understand why JAK2-positive myeloproliferative neoplasms (MPN) patients manifest different phenotypes despite harboring JAK2 mutations and what drives secondary transformations. PATIENTS AND METHODS: Using targeted sequencing, we analyzed mutational status of 17 polycythemia vera (PV), 16 essential thrombocythemia (ET), 8 primary myelofibrosis (PMF) patients who tested positive for JAK by polymerase chain reaction. RESULTS: The somatic mutations in JAK2 influence the clinical behavior of the disease. We found that ASXL1 or EZH2 mutation acquisition after JAK2 leads to PV, while ASXL1 mutation acquisition before JAK2 leads to ET or PMF. Mutations in TP53, ASXL1, and splicing genes are associated with the prognosis of MPN. PMF was more frequently associated with splicing mutations, while PV was more closely related to mutations in chromatin modifiers. The presence of these mutations influenced hemogram at MPN diagnosis. CONCLUSION: Each subtype of MPN harbors distinct patterns of somatic mutations and acquisition order, while mutations in TP53, ASXL1, and splicing genes may be associated with the prognosis of MPN.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Genes p53 , Janus Quinase 2/genética , Mutação , Policitemia Vera/genética , Mielofibrose Primária/genética , Proteínas Repressoras/genética , Trombocitemia Essencial/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Processamento de RNA
14.
Exp Hematol ; 79: 16-25.e3, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31678370

RESUMO

Megakaryocytes have been implicated in the micro-environmental abnormalities associated with fibrosis and hematopoietic failure in the bone marrow (BM) of primary myelofibrosis (PMF) patients, the Philadelphia-negative myeloproliferative neoplasm (MPN) associated with the poorest prognosis. To identify possible therapeutic targets for restoring BM functions in PMF, we compared the expression profiling of PMF BM with that of BM from essential thrombocytopenia (ET), a fibrosis-free MPN also associated with BM megakaryocyte hyperplasia. The signature of PMF BM was also compared with published signatures associated with liver and lung fibrosis. Gene set enrichment analysis (GSEA) identified distinctive differences between the expression profiles of PMF and ET. Notch, K-Ras, IL-8, and apoptosis pathways were altered the most in PMF as compared with controls. By contrast, cholesterol homeostasis, unfolded protein response, and hypoxia were the pathways found altered to the greatest degree in ET compared with control specimens. BM from PMF expressed a noncanonical transforming growth factor ß (TGF-ß) signature, which included activation of ID1, JUN, GADD45b, and genes with binding motifs for the JUN transcriptional complex AP1. By contrast, the expression of ID1 and GADD45b was not altered and there was a modest signal for JUN activation in ET. The similarities among PMF, liver fibrosis, and lung fibrosis were modest and included activation of integrin-α9 and tropomyosin-α1 between PMF and liver fibrosis, and of ectoderm-neural cortex protein 1 and FRAS1-related extracellular matrix protein 1 between PMF and lung fibrosis, but not TGF-ß. These data identify TGF-ß as a potential target for micro-environmental therapy in PMF.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Mielofibrose Primária/metabolismo , Transdução de Sinais , Trombocitemia Essencial/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia
15.
Genes (Basel) ; 10(10)2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618985

RESUMO

Myeloproliferative neoplasms (MPN) are genetically very complex and heterogeneous diseases in which the acquisition of a somatic driver mutation triggers three main myeloid cytokine receptors, and phenotypically expresses as polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The course of the diseases may be influenced by germline predispositions, modifying mutations, their order of acquisition and environmental factors such as aging and inflammation. Deciphering these contributory elements, their mutual interrelationships, and their contribution to MPN pathogenesis brings important insights into the diseases. Animal models (mainly mouse and zebrafish) have already significantly contributed to understanding the role of several acquired and germline mutations in MPN oncogenic signaling. Novel technologies such as induced pluripotent stem cells (iPSCs) and precise genome editing (using CRISPR/Cas9) contribute to the emerging understanding of MPN pathogenesis and clonal architecture, and form a convenient platform for evaluating drug efficacy. In this overview, the genetic landscape of MPN is briefly described, with an attempt to cover the main discoveries of the last 15 years. Mouse and zebrafish models of the driver mutations are discussed and followed by a review of recent progress in modeling MPN with patient-derived iPSCs and CRISPR/Cas9 gene editing.


Assuntos
Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/fisiopatologia , Animais , Calreticulina/genética , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Janus Quinase 2/genética , Camundongos , Mutação , Neoplasias/genética , Fenótipo , Policitemia Vera/genética , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Transdução de Sinais , Trombocitemia Essencial/genética , Peixe-Zebra
16.
Int J Hematol ; 110(6): 690-698, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571131

RESUMO

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are often characterized by specific somatic mutations in any of the three genes: JAK2, CALR, or MPL. A single nucleotide polymorphism (SNP), rs2736100, in the reverse transcriptase gene (TERT) and a germline JAK2 46/1 haplotype have been associated with MPNs in North American and European patients. We examined 201 Japanese MPN patients, including 52 with PV, 131 with ET, and 18 with PMF, as well as 366 control individuals for TERT rs2736100 and JAK2 rs10974944, a tagging SNP of the 46/1 haplotype. Furthermore, correlations between the JAK2 V617F allele burden at diagnosis and TERT rs2736100 or JAK2 rs10974944 were evaluated using a digital PCR assay for accurate quantitation. The JAK2 46/1 haplotype, but not the TERT rs2736100 SNP, was correlated to the JAK2 V617F mutant allele burden in JAK2 V617F-positive MPN patients. In conclusion, we demonstrated that both TERT rs2736100_C and JAK2 46/1 haplotype are predisposing factors for MPNs in Japanese patients. While TERT rs2736100_C tended to have a more general, non-specific effect on all MPNs, the JAK2 46/1 haplotype was essentially predisposed to the JAK2 V617F-positive MPNs.


Assuntos
Predisposição Genética para Doença , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Polimorfismo Genético , Telomerase/genética , Idoso , Estudos de Casos e Controles , Feminino , Haplótipos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Policitemia Vera/genética , Mielofibrose Primária/genética , Trombocitemia Essencial/genética
17.
PLoS One ; 14(9): e0222912, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31569199

RESUMO

To confirm that neoplastic monocyte-derived collagen- and fibronectin-producing fibrocytes induce bone marrow (BM) fibrosis in primary myelofibrosis (PMF), we injected PMF BM-derived fibrocyte-precursor CD14+/CD34- monocytes into the tail vein of NOD-SCID-γ (NSG) mice. PMF BM-derived CD14+/CD34- monocytes engrafted and induced a PMF-like phenotype with splenomegaly, myeloid hyperplasia with clusters of atypical megakaryocytes, persistence of the JAK2V617F mutation, and BM and spleen fibrosis. As control we used normal human BM-derived CD14+/CD34- monocytes. These monocytes also engrafted and gave rise to normal megakaryocytes that, like PMF CD14+/CD34--derived megakaryocytes, expressed HLA-ABC and human CD42b antigens. Using 2 clonogenic assays we confirmed that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte colony-forming cells, suggesting that a subpopulation BM monocytes harbors megakaryocyte progenitor capacity. Taken together, our data suggest that PMF monocytes induce myelofibrosis-like phenotype in immunodeficient mice and that PMF and normal BM-derived CD14+/CD34- monocytes give rise to megakaryocyte progenitor cells.


Assuntos
Células da Medula Óssea/imunologia , Fibroblastos/imunologia , Hiperplasia/imunologia , Hospedeiro Imunocomprometido , Monócitos/imunologia , Mielofibrose Primária/imunologia , Esplenomegalia/imunologia , Transferência Adotiva , Animais , Antígenos CD34/genética , Antígenos CD34/imunologia , Células da Medula Óssea/patologia , Feminino , Fibroblastos/patologia , Fibroblastos/transplante , Expressão Gênica , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Hiperplasia/etiologia , Hiperplasia/genética , Hiperplasia/patologia , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Megacariócitos/imunologia , Megacariócitos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Monócitos/patologia , Monócitos/transplante , Mutação , Mielofibrose Primária/etiologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Esplenomegalia/etiologia , Esplenomegalia/genética , Esplenomegalia/patologia
18.
Eur J Haematol ; 103(6): 552-557, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446640

RESUMO

INTRODUCTION: Primary and post-ET/PV myelofibrosis are myeloproliferative neoplasms harboring in most cases driving mutations in JAK2, CALR or MPL, and a variable number of additional mutations in other genes. Molecular analysis represents a powerful tool to guide prognosis and clinical management. Only about 10% of patients with myelofibrosis harbor alterations in MPL gene. No data are available about the transplantation outcome in the specific MPL-mutated group. PATIENTS: We collected the data of 18 myelofibrosis patients(primary: 14; post-ET: 4) transplanted in 4 EBMT centers (Hamburg, Paris, Essen, and Hannover) between 2005 and 2016. RESULTS: Before the transplant, we explored the molecular profile by NGS and reported the frequency of mutations occurring in a panel of genes including JAK2, MPL, CALR, U2AF1, SRSF2, SF3B1, ASXL1, IDH1, IDH2, CBL, DNMT3A, TET2, EZH2, TP53, IKZF1, NRAS, KRAS, FLT3, SH2B3, and RUNX1. The 1-year transplant-related mortality was 16.5%, 5-years overall survival and 5-y relapse-free survival 83.5%. The only relapse occurred in a patient who harbored mutations in both ASXL1 and EZH2 genes. CONCLUSION: These retrospective data suggest that MPL-mutated myelofibrosis patients have a favorable outcome after allogeneic transplantation with very low rate of disease relapse (5.5%) in comparison with the available historical controls regarding myelofibrosis in all.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mutação , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Mielofibrose Primária/terapia , Receptores de Trombopoetina/genética , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
20.
Ann Hematol ; 98(10): 2319-2328, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31396671

RESUMO

Triple-negative primary myelofibrosis (TN-PMF) and other myeloid neoplasms with associated bone marrow fibrosis such as the myelodysplastic syndromes (MDS-F) or the myelodysplastic/myeloproliferative neoplasms (MDS/MPN-F) are rare entities, often difficult to distinguish from each other. Thirty-four patients previously diagnosed with TN-PMF (n = 14), MDS-F (n = 18), or MDS/MPN-F (n = 2) were included in the present study. After central revision of the bone marrow histology, diagnoses according to the 2016-WHO classification were TN-PMF (n = 6), MDS-F (n = 19), and MDS/MPN-F (n = 9), with TN-PMF genotype representing only 4% of a cohort of 141 molecularly annotated PMF. Genomic classification according to next-generation sequencing and cytogenetic study was performed in 28 cases. Median number of mutations was 4 (range 1-7) in cases with TP53 disruption/aneuploidy or with chromatin-spliceosome mutations versus 1 mutation (range 0-2) in other molecular subgroups (p < 0.0001). The number of mutations and the molecular classification were better than PMF and MDS conventional scoring systems to predict survival and progression to acute leukemia. In conclusion, TN-PMF is an uncommon entity when the 2016 WHO criteria are strictly applied. Genomic classification may help in the prognostic assessment of patients with myeloid neoplasms with bone marrow fibrosis.


Assuntos
Neoplasias Hematológicas , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda , Mutação , Síndromes Mielodisplásicas , Mielofibrose Primária , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias Hematológicas/classificação , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Mielofibrose Primária/classificação , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Taxa de Sobrevida
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