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1.
Eur J Cancer ; 137: 224-234, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32799036

RESUMO

BACKGROUND: Chronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the incidence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients. PATIENTS AND METHODS: In the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP. RESULTS: With a median follow-up of 38 months (range: 2-190 months), the cumulative incidence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1-5%) and 7% (CI 95%: 4-11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haematopoietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome. CONCLUSION: Children evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis.

2.
Orphanet J Rare Dis ; 15(1): 180, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641076

RESUMO

BACKGROUND: Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis. RESULTS: A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients. CONCLUSION: The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients' healthcare and probably has to be democratized notably for complex cases.

3.
J Exp Med ; 217(9)2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32667968

RESUMO

Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αß T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.

5.
Bull Cancer ; 107(6): 629-632, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-155023

RESUMO

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.


Assuntos
Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/farmacocinética , Antivirais/uso terapêutico , Criança , Técnicas de Laboratório Clínico , Terapia Combinada , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Gerenciamento Clínico , Síndrome de Down/epidemiologia , Interações Medicamentosas , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/prevenção & controle , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Masculino , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Indução de Remissão , Risco , Medição de Risco , Terapia de Salvação , Avaliação de Sintomas
7.
Bull Cancer ; 107(6): 629-632, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32387061

RESUMO

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.


Assuntos
Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/farmacocinética , Antivirais/uso terapêutico , Criança , Técnicas de Laboratório Clínico , Terapia Combinada , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Gerenciamento Clínico , Síndrome de Down/epidemiologia , Interações Medicamentosas , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/prevenção & controle , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Masculino , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Indução de Remissão , Risco , Medição de Risco , Terapia de Salvação , Avaliação de Sintomas
8.
Blood ; 136(4): 387-400, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32344427

RESUMO

Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.

9.
Cancer Epidemiol ; 65: 101697, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32155583

RESUMO

BACKGROUND: On average 185 children are diagnosed each year in France with a cancer in their first year of life, representing 11 % of cancers diagnosed in children less than 15 years. METHODS: A retrospective population-based observational study was conducted between 2000 and 2014 of all infants with a diagnosis of cancer using the National Registry of Childhood Cancers Database. RESULTS: Out of 2760 cases of primary cancers in infancy, there were mainly neuroblastomas 30.1 %), central nervous system (CNS) tumors (16.1 %), leukemias (15.3 %), retinoblastomas (11.6 %), and Wilms tumors (6.9 %). Embryonal malignancies accounted for 55.2 % of cases. Most diagnoses showed a male excess, particularly for malignant gonadal germ-cell tumors (GCT) with a 17.5 sex-ratio. The annual incidence rate, 242.9 per million infants overall, was stable over the study period for all types of cancer. Most deaths occurred within the first month of life (70.8 % of deaths). The 5-year overall survival (5-y OS) was 81.0 % (95 %CI, 79.4-82.4) with large contrasts between diagnoses. The best 5-y OS (>85 %) were observed for retinoblastomas, carcinomas, nephroblastomas, GCT, neuroblastomas, and hepatoblastomas. Conversely, the lowest 5-y OS (<65 %) were observed for acute myeloid leukemias, CNS tumors, and lymphoid leukemias. We observed no substantial change over time (80.5 % [95 %CI, 77.7-82.9] in 2000-2004 and 82.6 % [95 %CI, 80.0-84.9] in 2010-2014) for all cancers combined. The same result has been found whatever the diagnostic group. CONCLUSION: Our results contribute to better understand these tumors by quantifying their impact on the French population and assessing the burden of some devastating infant cancers.


Assuntos
Neoplasias/epidemiologia , Feminino , França/epidemiologia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Neoplasias/mortalidade , Estudos Retrospectivos , Análise de Sobrevida
11.
Clin Infect Dis ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31773143

RESUMO

BACKGROUND: Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed safety and efficacy of fidaxomicin in children. METHODS: Patients aged <18 years with confirmed CDI were randomized 2:1 to ten days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, four times daily). Safety assessments included treatment-emergent adverse events (TEAEs). The primary efficacy endpoint was confirmed clinical response (CCR), 2 days after end of treatment (EOT). Secondary endpoints included global cure (GC; CCR without CDI recurrence) 30 days after EOT (end of study; EOS). Plasma and stool concentrations of fidaxomicin and its active metabolite OP-1118 were measured. RESULTS: Of 148 patients randomized, 142 were treated (30 <2 years old). The proportion of participants with TEAEs was similar with fidaxomicin (73.5%) and vancomycin (75.0%). Of three deaths in the fidaxomicin arm during the study, none were CDI or treatment related. The rate of CCR at 2 days after EOT was 77.6% (76/98) with fidaxomicin and 70.5% (31/44) with vancomycin, while the rate of GC at EOS was significantly higher in participants receiving fidaxomicin (68.4% versus 50.0%; adjusted treatment difference 18.8%; 95% CI 1.5%, 35.3%). Systemic absorption of fidaxomicin and OP-1118 was minimal and stool concentrations were high. CONCLUSIONS: Fidaxomicin was well tolerated and demonstrated significantly higher rates of GC, compared with vancomycin, in children and adolescents with CDI.

12.
Cancer Discov ; 9(12): 1736-1753, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31662298

RESUMO

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631.

13.
Blood Adv ; 3(13): 1981-1988, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31270080

RESUMO

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αß lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% (P = .177).

14.
Int J Cancer ; 145(11): 2907-2916, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30697705

RESUMO

Neuroblastoma (NB) is the most common extra-cranial tumour in children. Little is known about the aetiology of NB. The early age at onset and the embryonic nature suggest a role for perinatal exposures. We conducted a pooled analysis of two French national population-based case-control studies to explore whether there was an association between parental smoking and alcohol consumption and the risk of NB. The mothers of 357 NB cases and 1,783 controls from general population, frequency matched by age and sex, were interviewed on demographic, socioeconomic and perinatal characteristics, maternal reproductive story, and life-style and childhood environment. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. A meta-analysis of our findings with those of previous studies was also conducted. Maternal smoking during pregnancy was slightly more often reported for the cases (24.1%) than for the controls (19.7%) (OR 1.3 [95% CI 0.9-1.7]; summary OR from meta-analysis 1.1 [95% CI 1.0-1.3]. Paternal smoking in the year before child's birth were not associated with NB as independent exposure (OR 1.1 [95% CI 0.9-1.4] but the association was stronger when both parents reported having smoked during pregnancy (OR 1.5 [95% CI 1.1-2.1]. No association was observed with maternal alcohol intake during pregnancy (OR 1.0 [95% CI 0.8-1.4], summary OR from meta-analysis 1.0 [95% CI 0.9-1.2]. Our findings provide some evidence of an association between maternal smoking during pregnancy and NB and add another reason to recommend that women refrain from smoking during pregnancy.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Neuroblastoma/epidemiologia , Fumar Tabaco/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Exposição Materna/efeitos adversos , Razão de Chances , Exposição Paterna/efeitos adversos , Gravidez , Sistema de Registros , Fumar Tabaco/efeitos adversos
15.
Leukemia ; 33(2): 348-357, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30089916

RESUMO

Despite constant progress in prognostic risk stratification, children with acute myeloid leukemia (AML) still relapse. Treatment failure and subsequent relapse have been attributed to acute myeloid leukemia-initiating cells (LSC), which harbor stem cell properties and are inherently chemoresistant. Although pediatric and adult AML represent two genetically very distinct diseases, we reasoned that common LSC gene expression programs are shared and consequently, the highly prognostic LSC17 signature score recently developed in adults may also be of clinical interest in childhood AML. Here, we demonstrated prognostic relevance of the LSC17 score in pediatric non-core-binding factor AML using Nanostring technology (ELAM02) and RNA-seq data from the NCI (TARGET-AML). AML were stratified by LSC17 quartile groups (lowest 25%, intermediate 50% and highest 25%) and children with low LSC17 score had significantly better event-free survival (EFS: HR = 3.35 (95%CI = 1.64-6.82), P < 0.001) and overall survival (OS: HR = 3.51 (95%CI = 1.38-8.92), P = 0.008) compared with patients with high LSC17 scores. More importantly, the high LSC17 score was an independent negative EFS and OS prognosticator determined by multivariate Cox model analysis (EFS: HR = 3.42 (95% CI = 1.63-7.16), P = 0.001; OS HR = 3.02 (95%CI = 1.16-7.85), P = 0.026). In conclusion, we have demonstrated the broad applicability of the LSC17 score in the clinical management of AML by extending its prognostic relevance to pediatric AML.


Assuntos
Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia , Transcriptoma , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/classificação , Masculino , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Taxa de Sobrevida
18.
Aesthetic Plast Surg ; 42(4): 1059-1064, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29750320

RESUMO

BACKGROUND: Brachioplasties often culminate in unsightly scars that are a source of disappointment to patients. We aimed to evaluate the results of M-Y axilloplasty following massive weight loss. PATIENTS: We performed a retrospective assessment of our technique for brachioplasty with an M-Y axilloplasty in 159 female patients after massive weight loss. This retrospective study covered a study period of 10 years. METHOD: After substantial lipoaspiration, the incision is placed on the internal side of the arm, with an M-shaped axilloplasty. RESULTS: The satisfaction rate was 154/159 (97%) and 120/159 (75.5%) being happy with their esthetic results. Nineteen percent (30/159) of the patients had complications and 12/159 (7.5%) underwent a surgical revision. CONCLUSION: M-Y axilloplasty for brachioplasty is an effective procedure for treating women who are unhappy with their upper arms after massive weight loss. The satisfaction rate is high, and the result leaves no excess skin on the chest. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Assuntos
Braço/cirurgia , Axila/cirurgia , Técnicas Cosméticas , Procedimentos Cirúrgicos Reconstrutivos/métodos , Perda de Peso , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
19.
Blood ; 132(2): 187-196, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29692343

RESUMO

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (KIT, NRAS, KRAS, FLT3, JAK2, CBL). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age (P = .004) and inv(16) subtype (P = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference (P = .14). The repertoire of KIT, FLT3, and NRAS/KRAS variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival (P < 10-4), whereas the presence of a single signaling clone did not (P = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.


Assuntos
Evolução Clonal/genética , Fatores de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Mutação , Transdução de Sinais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Criança , Pré-Escolar , Aberrações Cromossômicas , Feminino , Regulação Leucêmica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
20.
Oncotarget ; 9(5): 6478-6489, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29464086

RESUMO

Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis. ZBTB7A mutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p. FOXP1 focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carried FOXP1 truncating mutations. Finally, CCDC26 disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia.

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