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1.
Rinsho Ketsueki ; 60(9): 1157-1165, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597839

RESUMO

The 8p11 myeloproliferative syndrome (EMS) is a relatively rare hematological malignancy defined by the presence of chromosomal abnormalities associated with fibroblast growth factor-1 gene, located in the 8p11-12.1 chromosomal locus. To date, only around a hundred cases have been reported in the literature. Patients with EMS present with various forms of myeloid/lymphoid malignancies, such as myeloproliferative neoplasms, acute myeloid leukemia, and T- or B-linage lymphoblastic lymphoma, which are frequently associated with eosinophilia. Prognosis of EMS is poor and a standard treatment strategy has not yet been established. In contrast to myeloid/lymphoid neoplasms associated with PDGFR-A or PDGFR-B rearrangement, the tyrosine kinase inhibitor (TKI) imatinib is not an effective therapeutic option for EMS patients. Other types of TKI, i.e., PKC412, sorafenib, ponatinib, dasatinib, and dovitinib, show growth-inhibitory effects against the cells harboring several types of FGFR-1 fusion genes in in vitro studies; however, the usefulness of either drug has not been confirmed by clinical trials. Therefore, at present, allo-hematopoietic stem cell transplantation is the only curative methods for EMS. Very recently, a phase-2 study with pemigatinib, an inhibitor for FGFR1, showed clinical benefits for EMS patients, including major cytogenetic response, suggesting a new therapeutic option for EMS.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 8/genética , Neoplasias Hematológicas/genética , Transtornos Mieloproliferativos/genética , Ensaios Clínicos Fase II como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores
2.
Anticancer Res ; 39(9): 4743-4748, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519574

RESUMO

BACKGROUND/AIM: Overexpression of human telomerase reverse transcriptase (hTERT) allows disordered proliferation and immortality of malignant cells, which has been of interest for the development of targeted therapies. The present study aimed to characterize hTERT gene expression in a series of cancer cell lines. MATERIALS AND METHODS: Leukemia cell lines K-562, its vincristine-resistant derivative K-562-Lucena1 and daunorubicin-resistant derivative FEPS; gastric adenocarcinoma lines AGP01, ACP02 and ACP03; melanoma SK-Mel-103 cells; and MN01 and MRC5, two non-neoplastic cell lines were analyzed by real-time polymerase chain reaction in order to evaluate hTERT gene expression. RESULTS: In leukemia cells, hTERT gene expression was significantly increased only in K-562 (p<0.05) and K-562-Lucena1 (p<0.001) when compared to the calibrator MRC5. For solid tumor types, only ACP03 presented a significant hTERT gene expression when compared to ACP02 (p<0.05). hTERT gene expression in K-562 and K-562-L ucena was significantly increased (p<0.05 to p<0.001) compared to all other cell lines except ACP03. CONCLUSION: In leukemia cell lines, hTERT gene overexpression was shown to be a potential target for pharmacological assays for drugs aiming to inhibit telomerase activity and control cell proliferation in oncohematological diseases.


Assuntos
Regulação Neoplásica da Expressão Gênica , Telomerase/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Neoplasias Hematológicas/genética , Humanos , Neoplasias/genética , Especificidade de Órgãos/genética
3.
Rinsho Ketsueki ; 60(8): 915-919, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484889

RESUMO

A 83-year-old female patient was admitted to our hospital due to hematological manifestation of juvenile granulocytes and macrocytic anemia. Bone marrow (BM) examination revealed erythroid dysplasia and cytoplasmic blasts, and hence the patient was diagnosed with myelodysplastic syndrome with ring sideroblasts and with single lineage dysplasia (MDS-RS-SLD). Erythrocyte transfusion was performed as a supportive therapy, and there was a gradual increase in the number of blood cells. Therefore, BM re-examination was performed and it was confirmed that the number of megakaryocytes increased, so the patient's condition was determined as myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN with RS-T). Incidentally, gene mutation analysis showed CALR gene mutation. Thereafter, administration of hydroxycarbamide and anagrelide did not show adverse events and complications, and a good blood count control was obtained. Furthermore, it was also confirmed that an SF3B1 gene mutation is highly positive in MDS-RS. There was no report on CALR-mutant MDS/MPN in Japan, and it is a rare disease overseas.


Assuntos
Calreticulina/genética , Neoplasias Hematológicas/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Trombocitose , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Mutação , Trombocitose/genética
4.
Crit Rev Oncol Hematol ; 142: 58-67, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377433

RESUMO

Single nucleotide polymorphism (SNP) microarrays are commonly used for the clinical investigation of constitutional genomic disorders; however, their adoption for investigating somatic changes is being recognised. With increasing importance being placed on defining the cancer genome, a shift in technology is imperative at a clinical level. Microarray platforms have the potential to become frontline testing, replacing or complementing standard investigations such as FISH or karyotype. This 'molecular karyotype approach' exemplified by SNP-microarrays has distinct advantages in the investigation of several haematological malignancies. A growing body of literature, including guidelines, has shown support for the use of SNP-microarrays in the clinical laboratory to aid in a more accurate definition of the cancer genome. Understanding the benefits of this technology along with discussing the barriers to its implementation is necessary for the development and incorporation of SNP-microarrays in a clinical laboratory for the investigation of haematological malignancies.


Assuntos
Neoplasias Hematológicas/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Humanos
5.
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
6.
Mol Biol (Mosk) ; 53(3): 456-466, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184611

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for hematopoietic malignancies. The graft-derived donor lymphocytes are capable of eliminating the residual recipient malignant cells in the course of allogeneic immune response, thus decreasing the chances of a relapse of the disease. Foreign peptides of the recipient presented by the MHC molecules are able to elicit the immune response immunologically. These polymorphic peptides are known as minor histocompatibility antigens (MiHAs). MiHAs occur due to the nonsynonymous single nucleotide polymorphisms in human genome. Transfusion of T cells specific to MiHAs presented predominantly in the cells of hematopoietic origin will allow the targeted elimination of residual malignant clones avoiding undesirable damage to healthy tissues. To induce the immune response, the donor must be homozygous by the MiHA allele and the recipient must either be homozygous or heterozygous by the alternative MiHA allele. The therapeutic mismatch occurs in 25% of cases under the optimal frequency of allelic variants. Minor antigen ACC-1Y originates from polymorphism in the BCL-2A1 gene; its immunogenic mismatch occurrence approaches the theoretical maximum. In addition, BCL2A1 is overexpressed in cells of various lymphomas. ACC-1Y is presented on allele HLA-A*24:02, which is relatively frequent in the Russian population. Combination of these factors makes the minor antigen ACC-1Y a promising target for immunotherapy. Transfusion of donor CD8^(+) lymphocytes modified with transgenic MiHA-specific TCR is one of the promising methods of posttransplant leukemia therapy and relapse prophylaxis. We obtained a sequence of high-affinity ACC-1Y-specific TCR after the antigen-specific expansion of T cells derived from a healthy ACC-IY^(-/-) donor. We cloned this sequence into the lentiviral vector and obtained the assembled viral particles. Further, we transduced the CD8^(+) lymphocyte culture and demonstrated its antigen-specific cytotoxic activity. It is suggested that CD8^(+) lymphocytes modified by the described method could be potentially transferred to recipients as a therapy against relapse after allo-HSCT.


Assuntos
Engenharia Celular , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Aloenxertos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Antígenos de Histocompatibilidade Menor/genética , Receptores de Antígenos de Linfócitos T/genética , Federação Russa , Prevenção Secundária/métodos
7.
Int J Mol Sci ; 20(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185671

RESUMO

Ultra-deep next-generation sequencing has emerged in recent years as an important diagnostic tool for the detection and follow-up of tumor burden in most of the known hematopoietic malignancies. Meticulous and high-throughput methods for the lowest possible quantified disease are needed to address the deficiencies of more classical techniques. Precision-based approaches will allow us to correctly stratify each patient based on the minimal residual disease (MRD) after a treatment cycle. In this review, we consider the most prominent ways to approach next-generation sequencing methodologies to follow-up MRD in hematological neoplasms.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Hematológicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Evolução Clonal , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , Neoplasia Residual
8.
Nat Commun ; 10(1): 2517, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175292

RESUMO

Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5BN642H, a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize the aggressive nature of STAT5BN642H in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5BN642H-driven transformation of γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5BN642H patient γδ T-cell entities. Importantly, we present human STAT5B and STAT5BN642H crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5BN642H can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5BN642H, conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5BN642H activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.


Assuntos
Linfócitos Intraepiteliais , Leucemia de Células T/genética , Linfoma de Células T/genética , Mutação , Fator de Transcrição STAT5/genética , Animais , Neoplasias Hematológicas/genética , Humanos , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Domínios de Homologia de src
9.
Int J Clin Oncol ; 24(8): 893-898, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111287

RESUMO

The development of allogeneic hematopoietic-stem-cell transplantation has improved the prognosis of younger acute myeloid leukemia (AML) patients. However, the outcome of older AML patients remains poor. The majority of AML patients are elderly. For elderly AML patients unfit for intensive chemotherapy, less toxic single agent that targets a specific gene mutation or combination therapy with a single agent is needed. The role of chromosomal abnormalities and genetic mutations in leukemia has become more apparent, and detailed prognostic stratification based on the type of genetic mutation has been established. Next-generation sequencing (NGS) has been used for gene analysis of AML. In the future, the evaluation of biologically homogeneous population on the basis of chromosomal abnormalities and gene mutations will lead to a paradigm shift that will help in the development of optimized therapy. As rapid diagnosis of gene mutations is required by the clinical physicians to decide on induction therapy, it is important to have a swift turnaround time for comprehensive DNA sequencing to provide actionable data to clinical physicians. It is required to conduct a feasibility study to evaluate the turnaround time from sending the specimens to receiving the results while maintaining the quality of the specimens contributing to gene analysis. To detect infrequent gene mutations, investigators need to perform multicenter studies and/or cooperative-group trials with a certain sample size to examine the frequency of the gene mutations in elderly AML patients, enabling sufficient statistical power for meaningful comparisons.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Medicina de Precisão , Neoplasias Hematológicas/genética , Humanos , Japão , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Prognóstico
10.
Int J Lab Hematol ; 41 Suppl 1: 131-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069978

RESUMO

Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.


Assuntos
Doenças Genéticas Inatas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Trombocitopenia , Aloenxertos , Genes Dominantes , Aconselhamento Genético , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia
11.
Int J Lab Hematol ; 41 Suppl 1: 142-150, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069979

RESUMO

Elevated peripheral blood (PB) cell counts, such as leukocytosis, thrombocytosis, and polycythemia, are often the presenting symptom in patients with myeloproliferative neoplasms (MPN). Because cythemias are nonspecific and may reflect either a reactive or neoplastic process, diagnostic workup of these patients is complicated and requires integration of numerous diagnostic modalities. Careful morphologic evaluation of the PB smear may provide insights into the underlying cause of the abnormal counts (such as the presence of teardrop erythrocytes in myelofibrosis or granulocytic dysplasia with left shift in atypical chronic myeloid leukemia). However, these morphologic findings need to be interpreted in concert with clinical findings and other laboratory results. In recent years, there has been a wealth of new genetic data in the field of MPN and many recurrent mutations have been identified, especially in cases lacking Philadelphia chromosome. Many of these genes impact the diagnosis and/or prognosis. Although certain mutations are preferentially enriched in specific MPN types, none of these mutations are disease defining; therefore, a thorough workup should always include a bone marrow biopsy for morphologic evaluation and diagnosis. This review will describe a comprehensive approach to the diagnosis of various MPN, with an emphasis on the diagnostic and prognostic implications of recurrent mutations in MPN.


Assuntos
Neoplasias Hematológicas , Mutação , Transtornos Mieloproliferativos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Prognóstico
12.
Int J Lab Hematol ; 41 Suppl 1: 117-125, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069982

RESUMO

Clinical genetic testing in the myeloid malignancies is undergoing a rapid transition from the era of cytogenetics and single-gene testing to an era dominated by next-generation sequencing (NGS). This transition promises to better reveal the genetic alterations underlying disease, but there are distinct risks and benefits associated with different NGS testing platforms. NGS offers the potential benefit of being able to survey alterations across a wider set of genes, but analytic and clinical challenges associated with incidental findings, germ line variation, turnaround time, and limits of detection must be addressed. Additionally, transcriptome-based testing may offer several distinct benefits beyond traditional DNA-based methods. In addition to testing at disease diagnosis, research indicates potential benefits of genetic testing both prior to disease onset and at remission. In this review, we discuss the transition from the era of cytogenetics and single-gene tests to the era of NGS panels and genome-wide sequencing-highlighting both the potential and drawbacks of these novel technologies.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Genômica/métodos , Neoplasias Hematológicas/genética , Transtornos Mieloproliferativos/genética , Análise de Sequência de DNA/métodos , Humanos
13.
Cas Lek Cesk ; 158(1): 22-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31046388

RESUMO

In patients with hematological malignancies one of the most substantial findings is the karyotype of bone marrow cells at the time of diagnosis. The detection of clonal chromosome aberrations in diagnostic samples not only confirms a neoplastic or premalignant process but also provides important diagnostic and prognostic information essential for precise disease classification and choice of suitable therapy. Karyotype analysis during the disease course also allows monitoring of the treatment success reflected as well in the revised WHO classification where patients are often classified into the different diagnostic subtypes based on the finding of specific chromosome and/or genetic changes. Recently, also increases the number of advanced treatment approaches that directly or indirectly target the genetic aberrations present in tumor cells. Despite the large development of new sequencing technologies in recent years, cytogenetic analysis supplemented by the molecular cytogenetic methods still remains a very important part of diagnostics of hematological malignancies.


Assuntos
Aberrações Cromossômicas , Análise Citogenética , Neoplasias Hematológicas , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Cariotipagem , Prognóstico
14.
Best Pract Res Clin Haematol ; 32(1): 98-103, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927980

RESUMO

Therapy-related myeloid neoplasms (t-MNs) are the most serious late complications in patients treated with traditional cytotoxic chemotherapy and/or radiation. T-MNs are aggressive and chemorefractory hematologic malignancies, with a median survival of less than 6 months. TP53 mutations are highly enriched in t-MN patients, though the mechanism for this selective enrichment has only come to light over the past several years. In this review, we discuss the history and function of p53, and the role of TP53 mutations in the origin and progression of t-MNs. Emerging data has begun to elucidate who may be at highest risk of developing t-MNs, which ideally will enable us to develop preventative strategies for this devastating disease. As t-MNs may not be avoidable, novel therapies are urgently needed for this patient group and are underway as exemplified by recent investigation in restoring wild-type p53 function as well as directly targeting TP53 mutant variants. With better prevention and treatment, outcomes will hopefully begin to improve in the near future.


Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Proteína Supressora de Tumor p53 , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/terapia , Proteína Supressora de Tumor p53/genética
16.
Best Pract Res Clin Haematol ; 32(1): 24-30, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927971

RESUMO

Therapy-related myeloid neoplasms (t-MNs) are one of the lethal complications from cytotoxic chemotherapy/radiation therapy. There is substantial variability in the risk of developing t-MNs among individuals who receive the same level of exposures and it has been widely suspected that germline polymorphisms may influence the risk and account for the variability. As the number of cancer survivors increases, effectively identifying an individual with a high risk of developing t-MNs is crucial. Here, we review the previous studies that investigated the association between germline polymorphisms and the risk of t-MNs. Through this process, we also discuss inconsistencies among the results that stem from the difficulties in conducting an appropriate study to link germline polymorphisms with a disease like t-MN that is rare and has a strong association with external exposures.


Assuntos
Células Germinativas , Neoplasias Hematológicas/genética , Transtornos Mieloproliferativos/genética , Segunda Neoplasia Primária/genética , Polimorfismo Genético , Feminino , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Masculino , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Segunda Neoplasia Primária/metabolismo , Fatores de Risco
17.
BMJ Case Rep ; 12(4)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31005862

RESUMO

A patient with a diagnosis of myelodysplastic syndrome (MDS) with isolated 5q deletion underwent repeat bone marrow biopsy to assess haematological response after 6 months of initial lenalidomide therapy. Subsequent bone marrow biopsies revealed persistent MDS with del(5q) in addition to a small atypical mast cell population with >25% of mast cells with spindle-shaped morphology and immunohistochemistry characteristics consistent with mastocytosis. Molecular testing on the bone marrow was positive for cKIT D816V and the patient was diagnosed with systemic mastocytosis (SM) with an associated haematological neoplasm. MDS with SM is well known to be associated; however, to the best of our knowledge, only one prior case report identifies MDS with del(5q) and associated cKIT D816V positive mastocytosis. While the exact clonal origin of both chromosomal aberrations is unclear, this case illustrates the therapeutic efficacy of lenalidomide in a patient with MDS with del(5q) and rarely associated cKIT positive SM.


Assuntos
Anemia Macrocítica/complicações , Neoplasias Hematológicas/complicações , Mastocitose/complicações , Síndromes Mielodisplásicas/complicações , Anemia Macrocítica/diagnóstico , Anemia Macrocítica/genética , Biópsia , Medula Óssea/patologia , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Fatores Imunológicos/administração & dosagem , Lenalidomida/administração & dosagem , Masculino , Mastocitose/diagnóstico , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia
18.
Best Pract Res Clin Haematol ; 32(1): 31-39, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927973

RESUMO

Therapy-related myeloid neoplasms are unintended and unwanted complications of cytotoxic chemotherapy and radiation. Unlike other environmental toxin-induced malignancies, exposure to the inciting agent is required to eradicate a primary and life-threatening cancer. In this review, we will focus on the biochemical mechanisms that lead to therapy-induced myeloid malignancy. This includes discussion of known mechanisms by which cytotoxic chemotherapy and radiation induce genetic mutations and promote evolution and expansion of malignant hematopoietic clones. Mechanisms by which the hematopoietic stem and progenitor microenvironment may be injured during the course of chemotherapy and radiation therapy will also be presented. While prevention strategies have not yet been brought into clinical testing or practice, there is active basic research relevant to prevention of t-MNs which is also included in our attempt to answer the question of whether we can do better to prevent stem cell injury after chemotherapy and radiation.


Assuntos
Neoplasias Hematológicas , Células-Tronco Hematopoéticas , Mutação , Transtornos Mieloproliferativos , Nicho de Células-Tronco , Microambiente Tumoral , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Radioterapia/efeitos adversos , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/genética , Nicho de Células-Tronco/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos da radiação
20.
Hematol Oncol ; 37(2): 205-211, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30849188

RESUMO

Systemic mastocytosis (SM) is a hematological malignancy characterized by extracutaneous infiltration by atypical mast cells. Together with indolent SM, aggressive SM, and mast cell leukemia, the World Health Organization (WHO) recognizes another major disease subgroup: SM with an associated hematological neoplasm, which is characterized by the presence of a concurrent neoplasm, more commonly, a chronic myelomonocytic leukemia. While KIT D816V is commonly regarded as the driver mutation, the clinical presentation of SM is extremely varied. Treatment of SM might not be simple, but now more specific therapies tailored toward prognostic subgroups of patients have been developed. Here, we report a detailed description of clinical management and biological features of a systemic mastocytocis case associated with multiple hematologic non-mast cell lineage diseases.


Assuntos
Neoplasias Hematológicas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mastocitose Sistêmica , Segunda Neoplasia Primária , Proteínas Proto-Oncogênicas c-kit/genética , Idoso , Substituição de Aminoácidos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Mastocitose Sistêmica/terapia , Mutação de Sentido Incorreto , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/terapia
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