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1.
Ann Hematol ; 98(10): 2379-2388, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31227872

RESUMO

A high impact of ARID5B SNPs on acute lymphoblastic leukemia (ALL) susceptibility has been described in Hispanic children; therefore, it is relevant to know if they influence the high incidence of childhood-ALL in Mexicans. Seven SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, rs4948488) of ARID5B were analyzed in 384 controls and 298 ALL children using genomic DNA and TaqMan probes. The SNPs were analyzed for deviation of Hardy-Weinberg equilibrium; Fisher's exact test was used to compare the genotypic and allelic frequencies between controls and patients. The association between SNPs and ALL susceptibility was calculated, and haplotype and ancestry analyses were conducted. All SNPs were associated with ALL, pre-B ALL, and hyperdiploid-ALL susceptibility (p < 0.05). No association with T-ALL and gene fusions was found (p > 0.05). The seven SNPs were associated with risk of pre-B ALL in younger children; however, rs2393732, rs2393782, rs2893881, and rs4948488 were not associated with susceptibility in older children and adolescents. The CAG haplotype (rs10821936, rs10994982, rs7089424) was strongly associated with ALL risk in our population (p < 0.00001). The frequency of all risk alleles in our ALL, pre-B, and hyperdiploid-ALL patients was higher than that in Hispanic children reported. This is the first report showing the association between rs2393732, rs2393782, and rs4948488 with pre-B hyperdiploid-ALL children. The G allele at rs2893881 confers major risk for pre-B hyperdiploid-ALL in Mexican (OR, 2.29) than in Hispanic children (OR, 1.71). The genetic background of our population could influence the susceptibility to ALL and explain its high incidence in Mexico.


Assuntos
Alelos , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Haplótipos , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Fatores de Transcrição/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Lactente , Masculino , México , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Fatores de Transcrição/metabolismo
2.
Nat Commun ; 10(1): 2789, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243274

RESUMO

IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.


Assuntos
Proteínas de Homeodomínio/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Animais , Apoptose , DNA/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genômica , Histonas , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Sequenciamento Completo do Genoma
3.
Medicine (Baltimore) ; 98(24): e15912, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192927

RESUMO

RATIONALE: The differential diagnosis of conditions manifesting as bone and joint pain is complex. Although many individuals with acute leukemia experience bone pain, lumbosacral pain as an early feature of acute lymphoblastic leukemia (ALL) is rare. PATIENT CONCERNS: Here we report a case of an adult who presented with a 7-month history of persistent lumbosacral pain which had become more severe during the previous month. DIAGNOSES: Prior to referral, his full blood count revealed no abnormalities, and a computerized tomography scan revealed mild bone hyperplasia of his lumbar vertebrae, with disc herniations of L3-S1. His blood biochemistry and urinary test results had been normal. After referral to our clinic, tests of the morphology, immunology, cytogenetics, and molecular biology of his bone marrow led to a diagnosis of MLL-AF4 fusion positive B-cell ALL. INTERVENTIONS: Prior to his referral, he had been treated with painkillers by local doctors. The painkillers initially provided pain relief, but their effect wore off over time. After diagnosis, he was started on an adult ALL chemotherapy protocol. OUTCOMES: His symptoms resolved within a week of starting chemotherapy. At his most recent assessment, 10 months after diagnosis, he was on maintenance chemotherapy and in remission. LESSONS: This case illustrates that prolonged lumbosacral pain may be a symptom of a life-threatening condition, rather than only attributable to chronic inflammation or disk herniations. Therefore, clinicians need to pay attention to subtle differences in the clinical presentation of patients with lumbosacral pain.


Assuntos
Deslocamento do Disco Intervertebral/diagnóstico por imagem , Dor Lombar/etiologia , Região Lombossacral/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adulto , Diagnóstico Diferencial , Tratamento Farmacológico , Humanos , Deslocamento do Disco Intervertebral/etiologia , Masculino , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Resultado do Tratamento
4.
J Clin Pathol ; 72(8): 558-561, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30948435

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.


Assuntos
Síndrome de Lange/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas/genética , Pré-Escolar , Análise Mutacional de DNA , Síndrome de Lange/diagnóstico , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Recidiva
5.
Proc Natl Acad Sci U S A ; 116(8): 3052-3061, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30733284

RESUMO

Glucocorticoids (GCs) are used in combination chemotherapies as front-line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although effective, many patients relapse and become resistant to chemotherapy and GCs in particular. Why these patients relapse is not clear. We took a comprehensive, functional genomics approach to identify sources of GC resistance. A genome-wide shRNA screen identified the transcriptional coactivators EHMT2, EHMT1, and CBX3 as important contributors to GC-induced cell death. This complex selectively supports GC-induced expression of genes contributing to cell death. A metaanalysis of gene expression data from B-ALL patient specimens revealed that Aurora kinase B (AURKB), which restrains GC signaling by phosphorylating EHMT1-2, is overexpressed in relapsed B-ALL, suggesting it as a potential contributor to relapse. Inhibition of AURKB enhanced GC-induced expression of cell death genes, resulting in potentiation of GC cytotoxicity in cell lines and relapsed B-ALL patient samples. This function for AURKB is distinct from its canonical role in the cell cycle. These results show the utility of functional genomics in understanding mechanisms of resistance and rapidly identifying combination chemotherapeutics.


Assuntos
Aurora Quinase B/genética , Morte Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/genética , Regulação Leucêmica da Expressão Gênica/genética , Glucocorticoides/genética , Glucocorticoides/farmacologia , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , RNA Interferente Pequeno/genética , Recidiva
6.
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
7.
Int J Hematol ; 109(4): 477-482, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30689137

RESUMO

ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3-27.0) and OS (HR 17.5; 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.


Assuntos
Asparaginase/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prednisolona/administração & dosagem , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Medição de Risco , Taxa de Sobrevida
8.
Oncogene ; 38(17): 3288-3300, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30631148

RESUMO

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with TCF3-PBX1 fusion gene expression has constitutively elevated levels of Wnt16b and ROR1 (receptor tyrosine kinase-like orphan receptor), a ligand and a receptor from the Wnt signaling pathway, respectively. Although survival rate is usually high after the initial chemotherapy, many TCF3-PBX1 BCP-ALL patients relapse and subsequently develop treatment resistance, resulting in poor prognosis. Here, we aimed to investigate the molecular signaling associated with Wnt16b and ROR1 overexpression in TCF3-PBX1 cell lines and primary samples, and to identify effective treatment options via ROR1 targeting. We detected higher ROR1 expression on TCF3-PBX1 leukemic cells even at a later stage of patient relapse, providing a strong rationale for the use of ROR1-targeted therapy. We found that Wnt5a-ROR1 signaling enhances proliferation of TCF3-PBX1 cells via RhoA/Rac1 GTPases activation and STAT3 upregulation. Wnt16b also activated the RhoA/Rac1 signaling cascade suggesting the activation of a non-canonical Wnt pathway in TCF3-PBX1 cells. Wnt16 could interact with ROR1 but not in TCF3-PBX1 cells, suggesting that Wnt5a is the ligand signaling via ROR1 in TCF3-PBX1 cells. By high throughput drug-sensitivity testing of TCF3-PBX1 cells before and after ROR1 knockdown we found that targeting ROR1 significantly improves the therapeutic efficacy of Bcl-2 family inhibitors venetoclax and navitoclax, and this synergism was confirmed ex vivo using a drug-resistant primary sample from a relapsed TCF3-PBX1 patient. Our work underlines a new type of targeted combination therapy that could be clinically advantageous for patients with TCF3-PBX1 BCP-ALL.


Assuntos
Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Via de Sinalização Wnt/genética , Proteína Wnt-5a/genética , Proteína rhoA de Ligação ao GTP/genética , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sulfonamidas/farmacologia , Taxa de Sobrevida , Translocação Genética/efeitos dos fármacos , Translocação Genética/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Via de Sinalização Wnt/efeitos dos fármacos
10.
Medicine (Baltimore) ; 97(42): e12763, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30334962

RESUMO

RATIONALE: A prolonged, prodromal phase before definitive paediatric precursor B acute lymphoblastic leukaemia (BCP ALL) diagnosis is rarely observed. PATIENTS CONCERNS: In the first, the patient presented with an aplastic preleukemic phase, whilst the second presented with a rheumatic-like preliminary phase. DIAGNOSES: The case reports of two patients with BCP ALL with a prodromal phase lasting a few weeks are presented. INTERVENTIONS AND OUTCOMES: DNA whole genome profile methylation analysis of bone marrow cells obtained at diagnosis revealed a pattern of methylation that was readily distinguishable from both healthy and standard course BCP ALL bone marrow samples. LESSONS: The biological implication of this observation remains unclear, with many differentially methylated loci involved in many processes like neurogenesis, cell projection organization and adhesion along with leucocyte activation and apoptosis. The prevalence and clinical significance of these methylation changes is unknown but this data indicates that the epigenetic basis of BCP ALL with a prolonged, prodromal phase requires a more detailed assessment.


Assuntos
Células da Medula Óssea/metabolismo , Metilação de DNA , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Sintomas Prodrômicos , Doença Aguda , Criança , Humanos , Masculino
11.
J Exp Clin Cancer Res ; 37(1): 204, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157922

RESUMO

BACKGROUND: Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear. METHODS: We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry. RESULTS: The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs. CONCLUSIONS: Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.


Assuntos
Citarabina/administração & dosagem , Células-Tronco Hematopoéticas/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Modelos Animais de Doenças , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/patologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Espécies Reativas de Oxigênio/metabolismo , Nicho de Células-Tronco/genética
12.
Cancer Genomics Proteomics ; 15(4): 299-312, 2018 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29976635

RESUMO

BACKGROUND/AIM: DNA methylation plays an important role in the initiation and propagation of carcinogenesis; however, the role of heterogeneously methylated epialleles is currently not well studied, also due to the lack of sensitive, unbiased and high throughput methods. Here, a newly developed droplet digital PCR (ddPCR)-based method was evaluated regarding its ability to quantify such heterogeneously methylated epialleles with sufficient analytical sensitivity and specificity. MATERIALS AND METHODS: Genomic DNA from blood leukocytes and bone marrow aspirate of an 8-year old male with B-cell acute lymphoblastic leukemia (B-ALL) and from normal and malignant prostate cell lines were analysed using ddPCR. RESULTS: By using these DNA samples, the specificity of an applied set of fluorescence-labeled probes was demonstrated as a proof of concept. CONCLUSION: All individual heterogeneously-methylated epialleles were quantifiable by a set of fluorescence-labeled probes with complementary sequences to epialleles in a closed-tube and high-throughput manner. The new method named epiallele-sensitive droplet digital PCR (EAST-ddPCR) may give new insights in the generation and regulation of epialleles and may help in finding new biomarkers for the diagnosis of benign und malignant diseases.


Assuntos
Alelos , Metilação de DNA , DNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Próstata/metabolismo , Biomarcadores Tumorais/genética , Células Cultivadas , Criança , DNA/análise , Heterogeneidade Genética , Humanos , Masculino , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Receptores da Fosfolipase A2/genética
13.
Int J Hematol ; 108(3): 312-318, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29786757

RESUMO

In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph+ B-ALL cell lines, the frequencies of IKZF1, CDKN2A/2B, BTG1, and PAX5 deletion were significantly higher than those in Ph- B-ALL cell lines. The frequency of CDKN2A/2B deletion in KMT2A rearranged cell lines was significantly lower than that in non-KMT2A rearranged cell lines. These findings suggest that CNAs are correlated with genetic subtype in B-ALL cell lines. In addition, we determined that three B-other ALL cell lines had IKZF1 deletions (YCUB-5, KOPN49, and KOPN75); we therefore performed comprehensive genetic analysis of these cell lines. YCUB-5, KOPN49, and KOPN75 had P2RY8-CRLF2, IgH-CRLF2, and PAX5-ETV6 fusions, respectively. Moreover, targeted capture sequencing revealed that YCUB-5 had JAK2 R683I and KRAS G12D, and KOPN49 had JAK2 R683G and KRAS G13D mutations. These data may contribute to progress in the field of leukemia research.


Assuntos
Variações do Número de Cópias de DNA/genética , Dosagem de Genes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Deleção de Genes , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Fator de Transcrição Ikaros/genética , Janus Quinase 2/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Proteínas Proto-Oncogênicas p21(ras)/genética
15.
Sci Rep ; 8(1): 693, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330417

RESUMO

Approximately 25% of the pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases are genetically unclassified. More thorough elucidation of the pathobiology of these genetically unclassified ('B-other') cases may identify novel treatment options. We analyzed gene expression profiles of 572 pediatric BCP-ALL cases, representing all major ALL subtypes. High expression of STAP1, an adaptor protein downstream of the B-cell receptor (BCR), was identified in BCR-ABL1-like and non-BCR-ABL1-like B-other cases. Limma analysis revealed an association between high expression of STAP1 and BCR signaling genes. However, STAP1 expression and pre-BCR signaling were not causally related: cytoplasmic Igµ levels were not abnormal in cases with high levels of STAP1 and stimulation of pre-BCR signaling did not induce STAP1 expression. To elucidate the role of STAP1 in BCP-ALL survival, expression was silenced in two human BCP-ALL cell lines. Knockdown of STAP1 did not reduce the proliferation rate or viability of these cells, suggesting that STAP1 is not a likely candidate for precision medicines. Moreover, high expression of STAP1 was not predictive for an unfavorable prognosis of BCR-ABL1-like and non-BCR-ABL1-like B-other cases. Remarkably, DUX4-rearrangements and intragenic ERG deletions, were enriched in cases harboring high expression of STAP1.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Homeodomínio/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Aberrações Cromossômicas , Proteínas de Fusão bcr-abl/genética , Humanos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
16.
Int J Hematol ; 107(5): 604-609, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29177615

RESUMO

ETV6-ABL1 fusion is a rare but recurrent oncogenic lesion found in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), without an established chromosomal abnormality, and is associated with poor outcome. In ETV6-ABL1-positive cases, an in-frame fusion produced by a complex rearrangement results in constitutive chimeric tyrosine kinase activity. Monosomy 7 is also a rare and unfavorable chromosomal abnormality in childhood BCP-ALL. Here, we report a 14-year-old female BCP-ALL patient with ETV6-ABL1 fusion combined with monosomy 7. She was admitted to our hospital because of persistent fever. Bone marrow nuclear cell count on admission was 855,000/µL with 90.0% blastic cells of lymphoid morphology. Blasts were positive for CD10, CD19, CD20, CD34, cyCD79a, cyTdT, HLA-DR, and CD66c, had a karyotype of 45, XX, - 7 [18/20] and a split signal for ABL1 FISH probe (92.7%), and were sensitive to tyrosine kinase inhibitors, imatinib and dasatinib, in vitro. ETV6-ABL1 fusion transcript was identified by whole transcriptome sequencing and confirmed by RT-PCR. She was treated with the high-risk protocol based on ALL-BFM 95, achieved complete remission (CR) after induction chemotherapy, and maintained CR for 4 months. To our knowledge, this is the first report of ETV6-ABL1 fusion combined with monosomy 7 in childhood BCP-ALL.


Assuntos
Dasatinibe/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia de Células B/genética , Proteínas Oncogênicas v-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Dasatinibe/farmacologia , Feminino , Fusão Gênica , Rearranjo Gênico/genética , Humanos , Mesilato de Imatinib/farmacologia , Quimioterapia de Indução , Quimioterapia de Manutenção , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Indução de Remissão
17.
Br J Haematol ; 180(4): 550-562, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29194562

RESUMO

To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10-5 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 +  for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 +  groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL.


Assuntos
Deleção Cromossômica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Deleção de Sequência , Adolescente , Fatores Etários , Biomarcadores Tumorais , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Medição de Risco , Fatores de Risco
18.
Hematol Oncol ; 36(1): 245-251, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28850694

RESUMO

Glucocorticoid (GC) shows antileukaemic activity via binding to the GC receptor (GR). The human GR gene has 4 splicing variants besides the functional isoform GRα, but their significance in GC sensitivity of acute lymphoblastic leukaemia (ALL) has been inconsistent. Additionally, several studies evaluated the relevance of GR gene single nucleotide polymorphisms (SNPs) in the GC sensitivity of ALL, but the current cumulative evidence appears inconclusive. Addressing limitations in previous studies, we used a large series of B-cell precursor ALL (BCP-ALL) cell lines established from Japanese patients to comprehensively examine all 5 splicing variants of the GR gene and candidate SNPs, and their association with GC-sensitivity. We performed real-time reverse transcription polymerase chain reaction (RT-PCR) analyses with 10 sets of primers that differentially quantify the 5 isoforms in different combinations, and the strongest correlations with GC sensitivity were observed for the real-time RT-PCR of exons 7 and 8 (prednisolone sensitivity; r = -0.534, R2  = 0.29, P = 1.4 × 10-6 ) and exons 8 and 9a (r = -0.583, R2  = 0.34, P = 7.6 × 10-8 ), both specific for GRα and GRγ isoforms. In contrast, the real-time RT-PCR of junction of exons 3g and 4 and exon 4, specific for GRγ isoform alone, did not show significant correlation with GC sensitivity (prednisolone sensitivity; r = -0.403, R2  = 0.16, P = 4.6 × 10-4 ). These observations are consistent with the notion that GRα plays a central role in the GC-mediated proapoptotic activity in BCP-ALL. In addition, a promoter region SNP genotype (rs72555796) showed a significant association with GC sensitivity (prednisolone sensitivity; P = .010) and tended to show an association with GR gene expression (RT-PCR of exons 7 and 8; P = .170). These findings indicate that isoform profiles and SNP genotypes of the GR gene may be useful indicators of GC sensitivity in BCP-ALL.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores de Glucocorticoides/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico
19.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28853218

RESUMO

BACKGROUND: We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians. PROCEDURE: Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346). RESULTS: The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02). CONCLUSIONS: Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B-precursor ALL.


Assuntos
GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Taxa de Sobrevida , Taiwan
20.
Br J Haematol ; 183(4): 588-600, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30596405

RESUMO

Given that FLT3 expression is highly restricted on lymphoid progenitors, it is possible that the established role of FLT3 in the regulation of B and T lymphopoiesis reflects its high expression and role in regulation of lymphoid-primed multipotent progenitors (LMPPs) or common lymphoid progenitors (CLPs). We generated a Flt3 conditional knock-out (Flt3fl/fl) mouse model to address the direct role of FLT3 in regulation of lymphoid-restricted progenitors, subsequent to turning on Rag1 expression, as well as potentially ontogeny-specific roles in B and T lymphopoiesis. Our studies establish a prominent and direct role of FLT3, independently of the established role of FLT3 in regulation of LMPPs and CLPs, in regulation of fetal as well as adult early B cell progenitors, and the early thymic progenitors (ETPs) in adult mice but not in the fetus. Our findings highlight the potential benefit of targeting poor prognosis acute B-cell progenitor leukaemia and ETP leukaemia with recurrent FLT3 mutations using clinical FLT3 inhibitors.


Assuntos
Células da Medula Óssea/metabolismo , Diferenciação Celular , Células Progenitoras Linfoides/metabolismo , Linfopoese , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Células da Medula Óssea/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Células Progenitoras Linfoides/patologia , Camundongos , Camundongos Knockout , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Timo/metabolismo , Timo/patologia , Tirosina Quinase 3 Semelhante a fms/genética
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