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1.
JAMA Oncol ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944221

RESUMO

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

2.
Pediatr Blood Cancer ; 67(1): e28040, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31612640

RESUMO

BACKGROUND: Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI). PROCEDURE: Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded. RESULTS: The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10-15 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4). CONCLUSION: Triglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.

3.
J Clin Oncol ; 37(35): 3377-3391, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31657981

RESUMO

PURPOSE: Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control. PATIENTS AND METHODS: Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m2 versus the conventional 2,500 U/m2. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction. RESULTS: The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; P = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] v 5.7% [95% CI, 2.8% to 8.6%]; P = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment. CONCLUSION: Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.

4.
Oncoimmunology ; 8(8): 1599637, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413907

RESUMO

T-cell malignancies expressing the γδ T-cell receptor (TCR) are often associated with poor prognosis. Here, we determined the clinical outcome of pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) expressing the γδ TCR. Of 100 newly diagnosed T-ALL patients, 93 had γδ TCR analysis performed at diagnosis. Repertoire was evaluated by paired sequencing of the rearranged TCR. All patients received intensified chemotherapy and those with minimal residual disease (MRD) ≥ 1% on day 42-46 became candidates for hematopoietic cell transplantation. Of the 93 T-ALL patients, 12 (13%) had γδ T-ALL and 11 (12%) had early T-cell precursor (ETP) ALL. Compared to the remaining 70 T-ALL patients, the γδ T-ALL patients were more likely to have MRD ≥ 1% on day 15-19 (67% vs. 33%, P = 0.03) and day 42-49 (33% vs. 7%; P = 0.007) of remission induction. The 10-year overall survival for γδ T-ALL patients (66.7% ± 22.2%) were lower than that of T-ALL patients (93.3% ± 7.3%, P = 0.001). TCR analysis demonstrated a conserved clonotype. In conclusion, the data suggest that children with γδ T-ALL may have a poor response to remission induction, based on MRD levels and decreased survival than the other T-ALL patients, despite receiving risk-directed therapy.

6.
J Clin Oncol ; 37(23): 2051-2061, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31188727

RESUMO

PURPOSE: Pegaspargase (PEG-ASP) has largely replaced native Escherichia coli asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome. PATIENTS AND METHODS: PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics. RESULTS: Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; P = 1.4 × 10-23). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions (P = 2.4 × 10-5), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance (P = 5.0 × 10-6). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP (P = .0078) and was predicted by the occurrence of angioedema with first reaction (P = .01). CONCLUSION: Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.

7.
Nat Genet ; 51(4): 694-704, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926971

RESUMO

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.


Assuntos
Leucemia Eritroblástica Aguda/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genômica/métodos , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Prognóstico , Proteína Supressora de Tumor p53/genética , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
8.
Pediatr Blood Cancer ; 66(6): e27669, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30758124

RESUMO

BACKGROUND: Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated. PROCEDURE: Patients with ALL on St. Jude Total Therapy XV (n = 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy. RESULTS: We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P = 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P = 0.00086) and arteriopathy (P = 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P = 0.00045) and arteriopathy (P = 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS. CONCLUSIONS: These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Bacteriemia/complicações , Dexametasona/efeitos adversos , Osteonecrose/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Índice de Gravidade de Doença , Animais , Criança , Seguimentos , Humanos , Incidência , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Osteonecrose/etiologia , Osteonecrose/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Tennessee/epidemiologia
9.
Nat Genet ; 51(2): 296-307, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643249

RESUMO

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.


Assuntos
Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Doença Aguda , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Cromossomos/genética , Feminino , Rearranjo Gênico/genética , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação/genética , Transcriptoma/genética , Adulto Jovem
10.
Cancer ; 125(6): 963-971, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521100

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.


Assuntos
Sistema Hematopoético/imunologia , Histiocitose de Células de Langerhans/complicações , Fígado/imunologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Baço/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/imunologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Prognóstico , Estudos Retrospectivos , Baço/patologia , Adulto Jovem
11.
JAMA Oncol ; 4(7): e180089, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29596541

RESUMO

Importance: Little is known about treatment-related neurotoxic mechanisms in children with acute lymphoblastic leukemia (ALL) treated with chemotherapy only. Objective: To examine concentration of cerebrospinal fluid (CSF) biomarkers of brain injury at ALL diagnosis and during cancer therapy and to evaluate associations with long-term neurocognitive and neuroimaging outcomes and relevant genetic polymorphisms. Design, Setting, and Participants: This prospective cohort study included 235 patients with ALL who received a chemotherapy-only protocol. Patients provided CSF samples after diagnosis and throughout treatment. At 5 or more years after the diagnosis, 138 (69.7%) of 198 eligible survivors participated in long-term follow-up assessments. Children were treated from June 1, 2000, through October 31, 2010. Follow-up was completed on October 21, 2014, and data were analyzed from August 1, 2015, through September 30, 2016. Exposures: Plasma concentration of high-dose intravenous methotrexate sodium and number of triple intrathecal chemotherapy injections. Main Outcomes and Measures: The CSF samples were assayed at 5 points from diagnosis to reinduction for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF] and total and phosphorylated tau protein), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuroinflammation (chitotriosidase). DNA was genotyped for polymorphisms in drug metabolism, oxidative stress, and neurodevelopment. Leukoencephalopathy was evaluated by brain imaging. At 5 or more years after the diagnosis, survivors completed neurocognitive testing and brain imaging of white matter integrity. Results: Among the 235 patients with CSF samples (120 boys [51.1%] and 115 girls [48.9%]; mean [SD] age at diagnosis, 6.8 [4.7] years), MBP and GFAP levels were elevated at baseline and through consolidation. The number of intrathecal injections was positively correlated with NGF level increase at consolidation (r = 0.19; P = .005). Increases in GFAP (risk ratio [RR], 1.23; 95% CI, 1.09-1.40), MBP (RR, 1.06; 95% CI, 1.01-1.11), and total tau (RR, 1.76; 95% CI, 1.11-2.78) levels were associated with a higher risk for leukoencephalopathy and higher apparent diffusion coefficient in frontal lobe white matter 5 years after diagnosis (standardized estimate, 0.05; P < .001). Increase in total tau at consolidation was associated with worse attention (omissions z score estimate, -0.20; P = .04). Conclusions and Relevance: Glial injury may be present at diagnosis of ALL. Neuronal injury was associated with intrathecal chemotherapy. The CSF biomarkers may be useful in identifying individuals at risk for worse neurologic outcomes, particularly those with genetic susceptibility to poor brain function.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Neuroimagem/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Traumatismos do Sistema Nervoso/diagnóstico , Encéfalo/patologia , Criança , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
12.
Cancer Manag Res ; 9: 397-410, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979163

RESUMO

Gene signatures have been associated with outcome in pediatric acute lymphoblastic leukemia (ALL) and other malignancies. However, determining the molecular drivers of these expression changes remains challenging. In ALL blasts, the p53 tumor suppressor is the primary regulator of the apoptotic response to genotoxic chemotherapy, which is predictive of outcome. Consequently, we hypothesized that the normal p53-regulated apoptotic response to DNA damage would be altered in ALL and that this alteration would influence drug response and treatment outcome. To test this, we first used global expression profiling in related human B-lineage lymphoblastoid cell lines with either wild type or mutant TP53 to characterize the normal p53-mediated transcriptional response to ionizing radiation (IR) and identified 747 p53-regulated apoptotic target genes. We then sorted these genes into six temporal expression clusters (TECs) based upon differences over time in their IR-induced p53-regulated gene expression patterns, and found that one cluster (TEC1) was associated with multidrug resistance in leukemic blasts in one cohort of children with ALL and was an independent predictor of survival in two others. Therefore, by investigating p53-mediated apoptosis in vitro, we identified a gene signature significantly associated with drug resistance and treatment outcome in ALL. These results suggest that intersecting pathway-derived and clinically derived expression data may be a powerful method to discover driver gene signatures with functional and clinical implications in pediatric ALL and perhaps other cancers as well.

13.
Nat Genet ; 49(8): 1211-1218, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28671688

RESUMO

Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Linhagem da Célula , Criança , Pré-Escolar , Estudos de Coortes , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Genômica , Humanos , Pessoa de Meia-Idade , Mutação , Receptor Notch1/metabolismo , Transdução de Sinais/genética , Adulto Jovem
14.
Pharmacogenomics ; 18(1): 5-16, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27967321

RESUMO

AIM: Identify the functional status of the uridine-diphosphate glucuronyl transferase 1A1 (UGT1A1) -3279T>G (*60) variant. MATERIALS & METHODS: Retrospective review of clinically obtained serum bilirubin concentrations in pediatric patients to evaluate the association of the UGT1A1 -3279T>G (*60) variant with bilirubin concentrations and assessed linkage disequilibrium of the UGT1A1 -3279T>G (*60) and A(TA)7TAA (*28) variants. RESULTS: Total bilirubin concentration did not differ between patients who had a UGT1A1*1/*1 diplotype and patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant. Total bilirubin concentration was lower in patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant than in patients homozygous for the UGT1A1 A(TA)7TAA (*28/*28) variant (p < 0.01). The -3279T>G (*60) and A(TA)7TAA (*28) variants were in strong incomplete linkage disequilibrium in both black and white patients. CONCLUSION: The presence of the UGT1A1 -3279T>G (*60) variant is not associated with increased bilirubin concentrations.


Assuntos
Alelos , Bilirrubina/sangue , Bilirrubina/genética , Glucuronosiltransferase/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Ligação Genética/genética , Doenças Hematológicas/sangue , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
15.
J Clin Oncol ; 35(4): 394-401, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27870571

RESUMO

Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico , Resultado do Tratamento , Adulto Jovem
16.
Nat Genet ; 48(12): 1481-1489, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27776115

RESUMO

Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt uses a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivation domains of ERG, but it inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia in which DUX4 deregulation results in loss of function of ERG, either by deletion or induced expression of an isoform that is a dominant-negative inhibitor of wild-type ERG function.


Assuntos
Transformação Celular Neoplásica/genética , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Proteínas de Homeodomínio/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Transformação Celular Neoplásica/patologia , Perfilação da Expressão Gênica , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Isoformas de Proteínas , Regulador Transcricional ERG/genética , Adulto Jovem
17.
Nat Commun ; 7: 13331, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27824051

RESUMO

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.


Assuntos
Genômica/métodos , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Sequência de Bases , Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico/genética , Inibidores de Histona Desacetilases/farmacologia , Humanos , Luciferases/metabolismo , Fatores de Transcrição MEF2/genética , Camundongos , Células NIH 3T3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Análise de Sequência de RNA , Transcriptoma , Resultado do Tratamento
18.
Sci Rep ; 6: 30757, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27476972

RESUMO

A feature in patients with constitutional DNA-mismatch repair deficiency is agenesis of the corpus callosum, the cause of which has not been established. Here we report a previously unrecognized consequence of deficiency in MSH2, a protein known primarily for its function in correcting nucleotide mismatches or insertions and deletions in duplex DNA caused by errors in DNA replication or recombination. We documented that Msh2 deficiency causes dysmyelination of the axonal projections in the corpus callosum. Evoked action potentials in the myelinated corpus callosum projections of Msh2-null mice were smaller than wild-type mice, whereas unmyelinated axons showed no difference. Msh2-null mice were also impaired in locomotive activity and had an abnormal response to heat. These findings reveal a novel pathogenic consequence of MSH2 deficiency, providing a new mechanistic hint to previously recognized neurological disorders in patients with inherited DNA-mismatch repair deficiency.


Assuntos
Corpo Caloso , Reparo de Erro de Pareamento de DNA , Doenças Desmielinizantes , Potenciais Evocados , Locomoção , Proteína 2 Homóloga a MutS/deficiência , Animais , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Corpo Caloso/fisiopatologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Camundongos , Camundongos Knockout , Proteína 2 Homóloga a MutS/metabolismo
19.
J Clin Oncol ; 34(30): 3708-3709, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27551120
20.
EBioMedicine ; 8: 173-183, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27428428

RESUMO

Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.


Assuntos
Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Genômica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma , Adolescente , Adulto , Idoso , Medula Óssea/patologia , Criança , Pré-Escolar , Análise por Conglomerados , Variações do Número de Cópias de DNA , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Pessoa de Meia-Idade , Mutação , Taxa de Mutação , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Adulto Jovem
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