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1.
Leukemia ; 34(8): 1984-1999, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32433508

RESUMO

Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21 , Síndrome de Down/complicações , Leucemia/genética , Animais , Criança , Síndrome de Down/tratamento farmacológico , Epigênese Genética , Humanos , Janus Quinase 2/genética , Leucemia/tratamento farmacológico , Leucemia/etiologia , Regulador Transcricional ERG/genética
2.
PLoS One ; 15(4): e0232597, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353063

RESUMO

The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility-both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation.


Assuntos
Causas de Morte , Leucemia/mortalidade , Neoplasias Induzidas por Radiação/mortalidade , Rádio (Elemento)/administração & dosagem , Retirada de Medicamento Baseada em Segurança , Espondilite Anquilosante/radioterapia , Tório/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Relação Dose-Resposta à Radiação , Seguimentos , Humanos , Injeções Intravenosas , Leucemia/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/etiologia , Dosagem Radioterapêutica , Rádio (Elemento)/efeitos adversos , Espondilite Anquilosante/mortalidade , Tório/efeitos adversos , Fatores de Tempo
3.
Ann Hematol ; 99(7): 1543-1550, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32430702

RESUMO

The major sources of the data on the hematological malignancies in the post-Chernobyl period in the regions of Ukraine differing by the levels of the residual contamination with radionuclides have been analyzed. According to the data collected from the primary hematological facilities in Ukraine in 2010-2017, the incidence of lymphoid neoplasms from mature B cells, acute myeloid leukemia, and multiple myeloma in the most contaminated regions was higher than in the less contaminated ones. For the first time, the relative contribution of the several specific types of leukemia in the total diagnosed hematological malignancies has been analyzed throughout 1997-2017 based on the in-house database compiled by the Reference Laboratory of RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine. In 2011-2017, the Reference Laboratory provided the diagnostic studies in about 26% of all Ukrainian patients with tumors of hematopoietic and lymphoid tissues (34% of patients with different forms of acute and chronic leukemia). The increased proportion of acute myeloid leukemia and chronic lymphocytic leukemia in the total diagnosed cases of overall leukemia in the patients from contaminated regions has been demonstrated following Chernobyl accident.


Assuntos
Acidente Nuclear de Chernobyl , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/etiologia , Neoplasias Induzidas por Radiação/epidemiologia , Bases de Dados Factuais , Feminino , História do Século XX , História do Século XXI , Humanos , Incidência , Leucemia/epidemiologia , Leucemia/etiologia , Linfoma/epidemiologia , Linfoma/etiologia , Masculino , Dados Preliminares , Cinza Radioativa/efeitos adversos , Cinza Radioativa/estatística & dados numéricos , Sistema de Registros , Ucrânia/epidemiologia
4.
Am J Hematol ; 95(7): 809-816, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32267023

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured.


Assuntos
Anemia de Fanconi , Transplante de Células-Tronco Hematopoéticas , Leucemia , Síndromes Mielodisplásicas , Doença Aguda , Aloenxertos , Intervalo Livre de Doença , Anemia de Fanconi/complicações , Anemia de Fanconi/mortalidade , Anemia de Fanconi/terapia , Feminino , Seguimentos , Humanos , Leucemia/etiologia , Leucemia/mortalidade , Leucemia/terapia , Masculino , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Taxa de Sobrevida
6.
J Exp Med ; 217(2)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31826240

RESUMO

Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott-Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/terapia , Terapia Genética/métodos , Imunodeficiência Combinada Severa/terapia , Síndrome de Wiskott-Aldrich/terapia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Animais , Edição de Genes , Técnicas de Transferência de Genes , Terapia Genética/efeitos adversos , Vetores Genéticos/genética , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Leucemia/etiologia , Mutagênese Insercional/métodos , Mutação de Sentido Incorreto , Retroviridae/genética , Linfócitos T/imunologia
7.
Blood Adv ; 3(24): 4238-4251, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31869411

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.


Assuntos
Células Dendríticas/patologia , Leucemia/diagnóstico , Leucemia/terapia , Doença Aguda , Biomarcadores , Contagem de Células Sanguíneas , Medula Óssea/patologia , Aberrações Cromossômicas , Evolução Clonal/genética , Células Dendríticas/metabolismo , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunofenotipagem , Leucemia/etiologia , Leucemia/metabolismo , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Resultado do Tratamento
8.
J Immunother Cancer ; 7(1): 355, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856922

RESUMO

Cytokines of the common γ-chain receptor family such as IL-15 are vital with respect to activating immune cells, sustaining healthy immune functions, and augmenting the anti-tumor activity of effector cells, making them ideal candidates for cancer immunotherapy. IL-15, either in its soluble form (IL-15sol) or complexed with IL-15Rα (IL-15Rc), has been shown to exhibit potent anti-tumor activities in various experimental cancer studies. Here we describe the impact of intraperitoneal IL-15 in a cancer cell-delivered IL-15 immunotherapy approach using the 70Z/3-L leukemia mouse model. Whereas both forms of IL-15 led to significantly improved survival rates compared to the parent cell line, there were striking differences in the extent of the improved survival: mice receiving cancer cells secreting IL-15sol showed significantly longer survival and protective long-term immunity compared to those producing IL-15Rc. Interestingly, injection of leukemia cells secreting IL-15sol lead to heightened expansion of CD4+ and CD8+ T-cell populations in the peritoneum compared to IL-15Rc. Cell-secreted IL-15Rc resulted in an influx and/or expansion of NK1.1+ cells in the peritoneum which was much less pronounced in the IL-15sol model. Furthermore, IL-15Rc but not IL-15sol lead to T-cell exhaustion and disease progression. To our knowledge, this is the first study detailing a significantly different biological effect of cell-delivered IL-15sol versus IL-15Rc in a mouse cancer immunotherapy study.


Assuntos
Imunomodulação , Imunoterapia , Interleucina-15/metabolismo , Leucemia/etiologia , Leucemia/metabolismo , Receptores de Interleucina-15/metabolismo , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Interleucina-15/sangue , Interleucina-15/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia/patologia , Leucemia/terapia , Melanoma Experimental , Camundongos , Ligação Proteica , Receptores de Interleucina-15/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transdução Genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Exp Clin Cancer Res ; 38(1): 406, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519186

RESUMO

Iron, an indispensable element for life, is involved in all kinds of important physiological activities. Iron promotes cell growth and proliferation, but it also causes oxidative stress damage. The body has a strict regulation mechanism of iron metabolism due to its potential toxicity. As a cancer of the bone marrow and blood cells, leukemia threatens human health seriously. Current studies suggest that dysregulation of iron metabolism and subsequent accumulation of excess iron are closely associated with the occurrence and progress of leukemia. Specifically, excess iron promotes the development of leukemia due to the pro-oxidative nature of iron and its damaging effects on DNA. On the other hand, leukemia cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide new insights for approaches to the treatment of leukemia. This review summarizes physiologic iron metabolism, alternations of iron metabolism in leukemia and therapeutic opportunities of targeting the altered iron metabolism in leukemia, with a focus on acute leukemia.


Assuntos
Ferro/metabolismo , Leucemia/etiologia , Leucemia/metabolismo , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Ferro/química , Leucemia/terapia , Redes e Vias Metabólicas/efeitos dos fármacos , Nanopartículas Metálicas/química , Terapia de Alvo Molecular , Oxirredução/efeitos dos fármacos , Estresse Oxidativo
10.
Immunobiology ; 224(5): 649-658, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31421859

RESUMO

Transforming growth factor-ß (TGF-ß) is known to function as a dual role regulatory cytokine for being either a suppresser or promoter during tumor initiation and progression. In solid tumors, TGF-ß secreted from tumor microenvironment acts as a suppresser against host immunity, like natural killer (NK) cells, to favor tumor evasion. However, besides solid tumors, the underlying mechanism of how TGF-ß regulates leukemogenesis, tumor progression, immunoediting, and NK function is still not clear in detail. In this study, we found that TGF-ß induced leukemia MEG-01 and U937 cells to become less sensitive to NK-92MI targeting by down-regulating CD48, a ligand for NK activating receptor 2B4, but not down-regulating other tumor-associated carbohydrate antigens (TACAs). In CD48-knockdown cells, cells responding to NK-92MI targeting displayed a phenotype of less NK susceptibility and cell conjugation. On the other hand, when NK cells were treated with TGF-ß, TGF-ß suppressed NK recognition, degranulation, and killing activity in time-dependent manner by regulating ICAM-1 binding capacity instead of affecting expressions of activating and inhibitory receptors. Taken together, both leukemia cells and immune NK cells could be regulated by TGF-ß through suppressing leukemia cell surface CD48 to escape from host surveillance and down-regulating NK cell surface ICAM-1 binding activity to impair NK functions, respectively. Our results suggested that TGF-ß had effect in leukemia similar to that observed in solid tumors but through different regulatory mechanism.


Assuntos
Antígeno CD48/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia/etiologia , Leucemia/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Antígeno CD48/genética , Degranulação Celular , Linhagem Celular Tumoral , Citotoxicidade Imunológica/efeitos dos fármacos , Suscetibilidade a Doenças , Humanos , Vigilância Imunológica , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Leucemia/patologia , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Receptores de Células Matadoras Naturais/metabolismo , Fator de Crescimento Transformador beta/farmacologia
12.
Radiat Res ; 192(5): 527-537, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31449440

RESUMO

While the link between risk of leukemia and acute radiation exposure is well established for large doses received acutely, uncertainty remains around the translation of these risk estimates to occupational exposure scenarios where the doses are low and accumulated over time, possibly over many years. We present leukemia incidence and mortality radiation risk estimates derived from the National Registry for Radiation Workers, which is a large cohort of occupationally exposed workers from the United Kingdom (UK). The cohort comprised 173,081 workers from the UK who were monitored for occupational exposure to radiation. The cohort was followed for a total of 5.3 million person-years and the incidence and mortality due to leukemia was identified through to the end of follow-up in 2011. Poisson regression was used to investigate the relationship between cumulative radiation dose and leukemia mortality and incidence rates using excess relative risk (ERR) and excess additive risk (EAR) models. The results of this work showed a collective dose of 4,414 person-Sv accumulated by the cohort with an average cumulative dose of 25.5 mSv. Among male workers both the ERR and EAR models showed evidence of increased leukemia risk (excluding chronic lymphatic leukemia) associated with increasing cumulative dose. The ERR was 1.38 per Sv (90% CI: 0.04; 3.24) and EAR was 1.33 per 10,000 person-year-Sv (90% CI: 0.04; 2.89) when a linear model was used. These excess risks were driven by increased risks for chronic myeloid leukemia [ERR/Sv = 6.77 (90% CI: 2.14; 15.44)]. In conclusion, this study provides further evidence that leukemia risks may be increased by low-dose and protracted external radiation exposure. The risks are generally consistent with those observed in the atomic bomb survivor studies, as well as with risk coefficients on which international radiation safety standards, including the dose limits and constraints used to control exposures, are based.


Assuntos
Leucemia Induzida por Radiação/epidemiologia , Leucemia Induzida por Radiação/etiologia , Leucemia/epidemiologia , Leucemia/etiologia , Proteção Radiológica/estatística & dados numéricos , Sistema de Registros , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Saúde do Trabalhador/estatística & dados numéricos , Doses de Radiação , Exposição à Radiação , Lesões por Radiação , Monitoramento de Radiação , Radiação Ionizante , Risco , Reino Unido
13.
Trends Mol Med ; 25(6): 494-515, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31109796

RESUMO

Aging leads to functional decline of the hematopoietic system, manifested by an increased incidence of hematological disease in the elderly. Deterioration of hematopoietic integrity with age originates in part from the degraded functionality of hematopoietic stem cells (HSCs). Here, we review recent findings identifying changes in metabolic programs and loss of epigenetic identity as major drivers of old HSC dysfunction and their role in promoting leukemia onset in the context of age-related clonal hematopoiesis (ARCH). We discuss how inflammatory and growth signals from the aged bone marrow (BM) microenvironment contribute to cell-intrinsic HSC aging phenotypes and favor leukemia development. Finally, we address how metabolic, epigenetic, and inflammatory pathways could be targeted to enhance old HSC fitness and prevent leukemic transformation.


Assuntos
Microambiente Celular , Senescência Celular , Células-Tronco Hematopoéticas/metabolismo , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Senescência Celular/genética , Desenho de Fármacos , Metabolismo Energético , Epigênese Genética , Regulação da Expressão Gênica , Hematopoese , Células-Tronco Hematopoéticas/citologia , Humanos , Leucemia/etiologia , Leucemia/metabolismo , Leucemia/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Microambiente Tumoral
14.
Am J Clin Nutr ; 109(Suppl_7): 757S-771S, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30982871

RESUMO

BACKGROUND: During the Pregnancy and Birth to 24 Months Project, the US Departments of Agriculture and Health and Human Services initiated a review of evidence on diet and health in these populations. OBJECTIVES: The aim of these systematic reviews was to examine the relation of 1) never versus ever feeding human milk, 2) shorter versus longer durations of any human milk feeding, 3) shorter versus longer durations of exclusive human milk feeding, and 4) feeding a lower versus higher intensity of human milk to mixed-fed infants with acute childhood leukemia, generally, and acute lymphoblastic leukemia, specifically. METHODS: The Nutrition Evidence Systematic Review team conducted systematic reviews with external experts. We searched CINAHL, Cochrane, Embase, and PubMed for articles published January 1980 to March 2016, dual-screened the results using predetermined criteria, extracted data from and assessed risk of bias for each included study, qualitatively synthesized the evidence, developed conclusion statements, and graded the strength of the evidence. RESULTS: We included 24 articles from case-control or retrospective studies. Limited evidence suggests that never feeding human milk versus 1) ever feeding human milk and 2) feeding human milk for durations ≥6 mo are associated with a slightly higher risk of acute childhood leukemia, whereas evidence comparing never feeding human milk with feeding human milk for durations <6 mo is mixed. Limited evidence suggests that, among infants fed human milk, a shorter versus longer duration of human milk feeding is associated with a slightly higher risk of acute childhood leukemia. None of the included articles examined exclusive human milk feeding or the intensity of human milk fed to mixed-fed infants. CONCLUSIONS: Feeding human milk for short durations or not at all may be associated with slightly higher acute childhood leukemia risk. The evidence could be strengthened with access to broadly generalizable prospective samples; therefore, we recommend linking surveillance systems that collect infant feeding and childhood cancer data.


Assuntos
Dieta , Comportamento Alimentar , Fórmulas Infantis , Leucemia , Leite Humano , Aleitamento Materno , Criança , Saúde da Criança , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Leucemia/etiologia , Leucemia/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevenção & controle
15.
Radiat Prot Dosimetry ; 184(3-4): 486-492, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31034559

RESUMO

In this paper, we revisit the possibility, first raised using a data set collected in the 1970s, that there is a link between average radon concentrations and the incidence of childhood leukaemia and lymphoma in Canada. Following the launch of the National Radon Program in 2007, Health Canada completed a long-term radon survey in 33 census metropolitan areas (CMAs), which covers about 70% of the Canadian population. We used this data, together with leukaemia and lymphoma incidence rates among children (0-14 years of age) in the past decade (2006-15), and tried to link the city-level average radon concentrations to the leukaemia and lymphoma incidence rates in 33 major Canadian cities. Analyses were conducted for six subtypes (ALL, AML, CMD, HL, NHL and BL) of leukaemia and lymphoma. Estimated doses to red bone marrow from domestic radon exposure were low and we did not find any association between radon exposure at home and the increased risk for developing leukaemia among children under 15 years of age living in the CMAs. The results indicate a slight positive association for AML among 1-4 year males in CMAs of Peer Group C and NHL among 5-9 year females in CMAs of Peer Group A; however, these should be interpreted with caution owing to the crude exposure assessment and possibilities of other confounding factors.


Assuntos
Poluentes Radioativos do Ar/efeitos adversos , Poluição do Ar em Ambientes Fechados/efeitos adversos , Leucemia/epidemiologia , Linfoma/epidemiologia , Neoplasias Induzidas por Radiação/epidemiologia , Exposição à Radiação/efeitos adversos , Radônio/efeitos adversos , Poluentes Radioativos do Ar/análise , Poluição do Ar em Ambientes Fechados/análise , Canadá/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Leucemia/etiologia , Leucemia/patologia , Linfoma/etiologia , Linfoma/patologia , Masculino , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/patologia , Monitoramento de Radiação/métodos , Radônio/análise , Fatores de Risco
16.
Blood ; 133(16): 1729-1741, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30755422

RESUMO

Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and ß receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis.


Assuntos
Células-Tronco Hematopoéticas/citologia , Proteínas de Homeodomínio/metabolismo , Leucemia/etiologia , Proteínas Repressoras/fisiologia , Animais , Carcinogênese , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Receptores de Interferon , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor
18.
Blood ; 133(10): 1031-1038, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30670448

RESUMO

Myelodysplastic syndrome (MDS) is characterized by bone marrow failure and a strong propensity for leukemic evolution. Somatic mutations are critical early drivers of the disorder, but the factors enabling the emergence, selection, and subsequent leukemic evolution of these "leukemia-poised" clones remain incompletely understood. Emerging data point at the mesenchymal niche as a critical contributor to disease initiation and evolution. Disrupted inflammatory signaling from niche cells may facilitate the occurrence of somatic mutations, their selection, and subsequent clonal expansion. This review summarizes the current concepts about "niche-facilitated" bone marrow failure and leukemic evolution, their underlying molecular mechanisms, and clinical implications for future innovative therapeutic targeting of the niche in MDS.


Assuntos
Células-Tronco Mesenquimais/citologia , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Nicho de Células-Tronco , Progressão da Doença , Predisposição Genética para Doença , Células-Tronco Hematopoéticas/citologia , Humanos , Inflamação , Leucemia/sangue , Leucemia/etiologia , Transdução de Sinais
19.
Int J Radiat Biol ; 95(7): 892-899, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30652952

RESUMO

Studies of the responses of hematopoietic stem and progenitor cells (HSPCs) to low doses of ionizing radiation formed an important aspect of the RISK-IR project ( www.risk-ir.eu ). A brief overview of these studies is presented here. The findings confirm the sensitivity of HSPCs to radiation even at low doses, and illustrate the substantial impact that differentiation state has upon cell sensitivity. The work provides mechanistic support for epidemiological findings of leukemia risk at dose levels used in diagnostic CT imaging, and further suggests that low-dose irradiation may facilitate bone marrow transplantation, a finding that could lead to refinements in clinical practice.


Assuntos
Células-Tronco Hematopoéticas/citologia , Leucemia/etiologia , Leucemia/radioterapia , Doses de Radiação , Radiação Ionizante , Células-Tronco/citologia , Animais , Diferenciação Celular/efeitos da radiação , Células Cultivadas , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Neoplasias Induzidas por Radiação , Tolerância a Radiação , Tomografia Computadorizada por Raios X
20.
Blood Cancer J ; 9(2): 12, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683837

RESUMO

Among 1306 patients with primary myelofibrosis (PMF), we sought to identify risk factors that predicted leukemic transformation (LT) in the first 5 years of disease and also over the course of the disease. 149 (11%) LT were documented; patients who subsequently developed LT (n = 149), compared to those who remained in chronic phase disease (n = 1,157), were more likely to be males (p = 0.02) and display higher circulating blasts (p = 0.03), ASXL1 (p = 0.01), SRSF2 (p = 0.001) and IDH1 (p = 0.02) mutations. Logistic regression analysis identified IDH1, ASXL1 and SRSF2 mutations, very high-risk karyotype, age > 70 years, male sex, circulating blasts ≥ 3%, presence of moderate or severe anemia and constitutional symptoms, as predictors of LT in the first 5 years of diagnosis. Time-to-event Cox analysis confirmed LT prediction for IDH1 mutation (HR 4.3), circulating blasts ≥ 3% (HR 3.3), SRSF2 mutation (HR 3.0), age > 70 years (HR 2.1), ASXL1 mutation (HR 2.0) and presence of moderate or severe anemia (HR 1.9). HR-based risk point allocation resulted in a three-tiered LT risk model: high-risk (LT incidence 57%; HR 39.3, 95% CI 10.8-114), intermediate-risk (LT incidence 17%; HR 4.1, 95% CI 2.4-7.3) and low-risk (LT incidence 8%). The current study provides a highly discriminating LT predictive model for PMF.


Assuntos
Transformação Celular Neoplásica , Leucemia/epidemiologia , Leucemia/etiologia , Mielofibrose Primária/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Progressão da Doença , Feminino , Humanos , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mielofibrose Primária/patologia , Prognóstico , Medição de Risco , Fatores de Risco , Adulto Jovem
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