RESUMO
Transient abnormal myelopoiesis (TAM) is a unique clonal myeloproliferation characterized by immature megakaryoblasts that occurs in 5-10% of neonates with Down syndrome (DS). Although TAM regresses spontaneously in most patients, approximately 20% of TAM cases result in early death, and approximately 20% of survivors develop acute megakaryoblastic leukemia (AMKL). We retrospectively reviewed records of 35 DS patients with TAM to determine the correlation between clinical characteristics and blast percentage. Thirteen of the 35 patients were classified as low blast percentage TAM (LBP-TAM), defined as TAM with a peak peripheral blast percentage ≤ 10%. Although no patient with LBP-TAM experienced systemic edema, disseminated intravascular coagulation, or early death, eight patients had elevated direct bilirubin levels (> 2 mg/dl) and one developed AMKL. All patients with LBP-TAM had serum markers of liver fibrosis that exceeded the normal limits, and two patients underwent liver biopsy to clarify the etiology of pathological jaundice. Taken together, our results suggest that patients with LBP-TAM may be at risk of liver fibrosis and liver failure, similarly to patients with classical TAM. Although these patients generally have a good prognosis, they should be carefully monitored for potential development of liver disease and leukemia.
Assuntos
Síndrome de Down/complicações , Reação Leucemoide/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Down/sangue , Feminino , Humanos , Lactente , Reação Leucemoide/sangue , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
Human herpesvirus-6 (HHV-6) is a common pathogen affecting the human population. Primary HHV-6 infection generally occurs during infancy and causes exanthema subitum. Moreover, HHV-6 may exhibit inherited chromosomally integrated HHV-6 (iciHHV-6) in certain individuals. Although iciHHV-6 is generally known to be nonpathogenic, it may cause reactivation in patients with primary immunodeficiency disease (PID). XIAP deficiency is a rare PID characterized by recurrent hemophagocytic lymphohistiocytosis (HLH). It has been reported that the Epstein-Barr virus primarily causes HLH; however, the other pathogens, including HHV-6, can also cause this complication. We encountered a case of XIAP deficiency accompanied by iciHHV-6. He suffered from recurrent HLH, for which allogeneic bone marrow transplantation (BMT) was performed as a curative therapy. During the course of BMT, the patient experienced HLH three times, but there was no reactivation of endogenous HHV-6 from iciHHV-6. Finally, the patient achieved complete donor chimerism and a decline in HHV-6 DNA copy number in whole blood. This case report demonstrates no evidence of reactivation of iciHHV-6 during BMT in a patient with XIAP deficiency.
Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 6 , Doenças Genéticas Ligadas ao Cromossomo X , Herpesvirus Humano 4 , Humanos , Transtornos Linfoproliferativos , Masculino , Integração Viral , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo XRESUMO
Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic µ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.
Assuntos
Ribonucleoproteínas Nucleares Heterogêneas , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Translocação Genética , Adolescente , Criança , Intervalo Livre de Doença , Feminino , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , 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 , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Taxa de SobrevidaAssuntos
Biomarcadores Tumorais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Mutação , Subunidade alfa 2 de Fator de Ligação ao Core/química , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Estudos de Associação Genética , Humanos , Leucemia Mieloide Aguda/metabolismo , PrognósticoRESUMO
High PRDM16 (also known as MEL1) expression is a representative marker of acute myeloid leukemia (AML) with NUP98-NSD1 and is a significant predictive marker for poor prognosis in pediatric AML. However, the clinical features of adult AML with PRDM16 expression remain unclear. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of MECOM (also known as EVI1). We investigated PRDM16 expression in 151 AML patients, with 47 (31%) exhibiting high PRDM16 expression (PRDM16/ABL1 ratio ≥ 0.010). High PRDM16 expression significantly correlated with DNMT3A (43% vs. 15%, P < 0.001) and NPM1 (43% vs. 21%, P = 0.010) mutations and partial tandem duplication of KMT2A (22% vs. 1%, P < 0.001). Remarkably, high-PRDM16-expression patients were frequent in the noncomplete remission group (48% vs. 21%, P = 0.002). Overall survival (OS) was significantly worse in high-PRDM16-expression patients than in low-PRDM16-expression patients (5-year OS, 18% vs. 34%; P = 0.002). This trend was observed more clearly among patients aged <65 years (5-year OS, 21% vs. 50%; P = 0.001), particularly in FLT3-ITD-negative patients in the intermediate cytogenetic risk group (5-year OS, 25% vs. 59%; P = 0.009). These results suggest that high PRDM16 expression is a significant predictive marker for poor prognosis in adult AML patients, similar to pediatric AML patients.
Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/metabolismo , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Fatores de Transcrição/metabolismo , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Pediatric acute megakaryoblastic leukemia in non-Down syndrome (AMKL) is a unique subtype of acute myeloid leukemia (AML). Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL were recently reported as poor prognostic factors. However, their detailed clinical and molecular characteristics in patients treated with recent improved therapies remain uncertain. We analyzed molecular features of 44 AMKL patients treated on two recent Japanese AML protocols, the AML99 and AML-05 trials. We identified CBFA2T3-GLIS2, NUP98-KDM5A, RBM15-MKL1, and KMT2A rearrangements in 12 (27%), 4 (9%), 2 (5%), and 3 (7%) patients, respectively. Among 459 other AML patients, NUP98-KDM5A was identified in 3 patients, whereas CBFA2T3-GLIS2 and RBM15-MKL1 were only present in AMKL. GATA1 mutations were found in 5 patients (11%). Four-year overall survival (OS) and event-free survival (EFS) rates of CBFA2T3-GLIS2-positive patients in AMKL were 41.7% and 16.7%, respectively. Three-year cumulative incidence of relapse in CBFA2T3-GLIS2-positive patients was significantly higher than that of CBFA2T3-GLIS2-negative patients (75.0% vs. 35.7%, P = 0.024). In multivariate analyses, CBFA2T3-GLIS2 was an independent poor prognostic factor for OS (HR, 4.34; 95% CI, 1.31-14.38) and EFS (HR, 2.95; 95% CI, 1.20-7.23). Furthermore, seven (54%) of 13 infant AMKL patients were CBFA2T3-GLIS2-positive. Notably, out of 7 CBFA2T3-GLIS2-positive infants, six (86%) relapsed and five (71%) died. Moreover, all of CBFA2T3-GLIS2-positive patients who experienced induction failure (n = 3) were infants, indicating worse prognosis of CBFA2T3-GLIS2-positive infants. These findings indicated the significance of CBFA2T3-GLIS2 as a poor prognostic factor in AMKL patients, particularly in infants.
Assuntos
Biomarcadores Tumorais/genética , Síndrome de Down/genética , Leucemia Megacarioblástica Aguda/genética , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Leucemia Megacarioblástica Aguda/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years). We identified 9 (2.4%) ASXL1 and 17 (4.6%) ASXL2 mutations in 25 patients. These mutations were more common in patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 (ASXL1, 6/9, 67%, P = 0.02; ASXL2, 10/17, 59%, P = 0.01). Among these 25 patients, 4 (27%) of 15 patients with t(8;21) and 6 (60%) of 10 patients without t(8;21) relapsed. However, most patients with relapse were rescued using stem cell transplantation irrespective of t(8;21). The overall survival (OS) and event-free survival (EFS) rates showed no differences among pediatric AML patients with t(8;21) and ASXL1 or ASXL2 mutations and ASXL wild-type (5-year OS, 75% vs. 100% vs. 91% and 5-year EFS, 67% vs. 80% vs. 67%). In 106 patients with t(8;21) AML, the coexistence of mutations in tyrosine kinase pathways and chromatin modifiers and/or cohesin complex component genes had no effect on prognosis. These results suggest that ASXL1 and ASXL2 mutations play key roles as cooperating mutations that induce leukemogenesis, particularly in pediatric AML patients with t(8;21), and these mutations might be associated with a better prognosis than that reported previously.
Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Translocação Genética/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1 , Taxa de SobrevidaRESUMO
Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence.
Assuntos
Evolução Clonal/genética , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Criança , Análise Mutacional de DNA , Progressão da Doença , Epigênese Genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Nucleofosmina , Prognóstico , RecidivaRESUMO
Recent reports described the NUP98-NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98-NSD1 fusion. PRDM16 gene expression levels were measured via real-time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P < 0·001; inv(16), 0% vs. 100%, P < 0·001; KMT2A (also termed MLL)- partial tandem duplication, 100% vs. 0%, P < 0·001; NUP98-NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than in patients with low PRDM16 expression (3-year OS: 51% vs. 81%, P < 0·001, 3-year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3-internal tandem duplication-positive AML patients (3-year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate-risk cytogenetic profiles and was independently associated with an adverse outcome.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Feminino , Expressão Gênica/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Mutação/genética , Proteína de Leucina Linfoide-Mieloide/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Nucleofosmina , Prognóstico , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Mutations in the colony-stimulating factor 3 receptor (CSF3R) and calreticulin (CALR) genes have been reported in a proportion of adults with myeloproliferative disease. However, little is known about CSF3R or CALR mutations in paediatric myeloid disorders. We analysed CSF3R exons 14 and 17, and CALR exon 9, using direct sequencing in samples of paediatric acute myeloid leukaemia (AML; n = 521), juvenile myelomonocytic leukaemia (JMML; n = 40), myelodysplastic syndrome (MDS; n = 20) and essential thrombocythaemia (ET; n = 21). CSF3R mutations were found in 10 (1.2%) of 521 patients with AML; two in exon 14 (both missense mutations resulting in p.T618I) and eight in exon 17 (three frameshift mutations: p.S715X, p.Q774R, and p.S783Q; and five novel missense mutations: p.Q754K, p.R769H, p.L777F, p.T781I, and S795R). All of the patients with mutations in CSF3R exon 17 had chromosomal translocations, including four with t(8;21). At the time of reporting, seven of these ten patients are alive; three have died, due to side effects of chemotherapy. No CSF3R mutations were found in cases of MDS, JMML or ET. The only mutation found in the CALR gene was a frameshift (p.L367 fs) in one ET patient. We discuss the potential impact of these findings for the leukaemogenesis and clinical features of paediatric myeloid disorders.
Assuntos
Calreticulina/genética , Mutação da Fase de Leitura , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Receptores de Fator Estimulador de Colônias/genética , Trombocitemia Essencial/genética , Translocação Genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Éxons , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/mortalidade , Masculino , Síndromes Mielodisplásicas/mortalidade , Trombocitemia Essencial/mortalidadeRESUMO
Pleuropulmonary blastoma (PPB) is a rare pediatric malignancy whose pathogens are poorly understood. Recent reports suggest that germline mutations in the microRNA-processing enzyme DICER1 may contribute to PPB development. To investigate the genetic basis of this cancer, we performed whole-exome sequencing or targeted deep sequencing of multiple cases of PPB. We found biallelic DICER1 mutations to be very common, more common than TP53 mutations also found in many tumors. Somatic ribonuclease III (RNase IIIb) domain mutations were identified in all evaluable cases, either in the presence or absence of nonsense/frameshift mutations. Most cases had mutated DICER1 alleles in the germline with or without an additional somatic mutation in the remaining allele, whereas other cases displayed somatic mutations exclusively where the RNase IIIb domain was invariably affected. Our results highlight the role of RNase IIIb domain mutations in DICER1 along with TP53 inactivation in PPB pathogenesis.
Assuntos
RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa , Neoplasias Pulmonares/genética , Blastoma Pulmonar/genética , Ribonuclease III/genética , Alelos , Análise Mutacional de DNA , Exoma , Frequência do Gene , Humanos , Neoplasias Pulmonares/enzimologia , Inclusão em Parafina , Polimorfismo de Nucleotídeo Único , Blastoma Pulmonar/enzimologia , Proteína Supressora de Tumor p53/genéticaRESUMO
Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells, which resolves spontaneously. Approximately 20 % of patients with TAM die at an early age due to organ failure, including liver disease. We studied 25 DS-TAM patients retrospectively to clarify the correlation between clinical and laboratory characteristics and liver diseases. Early death (<6 months of age) occurred in four of the 25 patients (16.0 %), and two of those four patients died due to liver failure. Although physiologic jaundice improved gradually after a week, all DS patients had elevated D-Bil levels during the clinical course of TAM, except one who suffered early death. The median peak day of the WBC count, total bilirubin (T-Bil) and D-Bil levels was: day 1 (range day 0-57), day 8 (range day 1-55), and day 17 (range 1-53), respectively. Our results reveal that all patients with DS-TAM may develop liver disease irrespective of the absence or presence of symptoms and risk factors for early death. In patients of DS-TAM, careful observation of the level of D-Bil is needed by at least 1 month of age for the detection of liver disease risk.
Assuntos
Síndrome de Down/fisiopatologia , Insuficiência Hepática/etiologia , Reação Leucemoide/fisiopatologia , Fígado/fisiopatologia , Progressão da Doença , Feminino , Insuficiência Hepática/congênito , Insuficiência Hepática/epidemiologia , Insuficiência Hepática/fisiopatologia , Hospitais Pediátricos , Humanos , Recém-Nascido , Japão/epidemiologia , Masculino , Insuficiência de Múltiplos Órgãos/epidemiologia , Insuficiência de Múltiplos Órgãos/etiologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaAssuntos
Proteínas de Transporte/genética , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Juvenil/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Nucleares/genética , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Proteínas Nucleares/metabolismoAssuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Fator de Transcrição GATA2/genética , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda/genética , Adolescente , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Dados de Sequência MolecularRESUMO
Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).
Assuntos
Síndrome de Down/genética , Síndrome de Down/imunologia , Leucemia Megacarioblástica Aguda/genética , Reação Leucemoide/genética , Sequência de Bases , Fator de Ligação a CCCTC , Proteínas de Ciclo Celular/genética , Proliferação de Células , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos Par 21/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Fator de Transcrição GATA1/genética , Perfilação da Expressão Gênica , Humanos , Células Mieloides , Transtornos Mieloproliferativos/genética , Proteínas Nucleares/genética , Complexo Repressor Polycomb 2/genética , Proteínas Repressoras/genética , Análise de Sequência de DNA , CoesinasRESUMO
Mutations in Wilms tumor 1 (WT1) have been reported in 10-22 % of patients with cytogenetically normal acute myeloid leukemia (CN-AML), but the prognostic implications of these abnormalities have not been clarified in either adults or children. One hundred and fifty-seven pediatric AML patients were analyzed for WT1 mutations around hotspots at exons 7 and 9; however, amplification of the WT1 gene by the reverse transcriptase-polymerase chain reaction was not completed in four cases (2.5 %). Of the 153 evaluable patients, 10 patients (6.5 %) had a mutation in WT1. The incidence of WT1 mutations was significantly higher in CN-AML than in others (15.2 vs. 4.5 %, respectively, P = 0.03). Of the 10 WT1-mutated cases, eight (80 %) had mutations in other genes, including FLT3-ITD in two cases, FLT3-D835 mutation in two, KIT mutation in three, MLL-PTD in three, NRAS mutation in one, and KRAS mutation in two (in some cases, more than one additional gene was mutated). The incidences of KIT and FLT3-D835 mutations were significantly higher in patients with than in those without WT1 mutation. No significant differences were observed in the 3-year overall survival and disease-free survival; however, the presence of WT1 mutation was related to a poor prognosis in patients with CN-AML, excluding those with FLT3-ITD and those younger than 3 years.
Assuntos
Leucemia Mieloide Aguda/genética , Mutação , Proteínas WT1/genética , Adolescente , Povo Asiático/genética , Criança , Pré-Escolar , Bandeamento Cromossômico , Feminino , Expressão Gênica , Humanos , Lactente , Recém-Nascido , Japão , Cariotipagem , Leucemia Mieloide Aguda/mortalidade , Masculino , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Mutations in the ATP6V1B1 and the ATP6V0A4 genes cause primary autosomal-recessive distal renal tubular acidosis (dRTA). Large deletions of either gene in patients with dRTA have not been described. METHODS: The ATP6V1B1 and ATP6V0A4 genes were directly sequenced in 11 Japanese patients with primary dRTA from nine unrelated kindreds. Large heterozygous deletions were analyzed by quantitative real-time polymerase chain reaction (PCR). The clinical features of the 11 patients were also investigated. RESULTS: Novel mutations in the ATP6V1B1 gene were identified in two kindreds, including frameshift, in-frame insertion and nonsense mutations. Large deletions in the ATP6V0A4 gene were identified in two kindreds. Exon 15 of ATP6V0A4 was not amplified in one patient, with a long PCR confirming compound heterozygous deletions of 3.7- and 6.9-kb nucleotides, including all of exon 15. Direct DNA sequencing revealed a heterozygous frameshift mutation in ATP6V0A4 in another patient, with quantitative real-time PCR indicating that all exons up to exon 8 were deleted in one allele. Clinical investigation showed that four of the six patients with available clinical data presented with hyperammonemia at onset. CONCLUSIONS: To our knowledge, these dRTA patients are the first to show large deletions involving one or more entire exons of the ATP6V0A4 gene. Quantitative PCR amplification may be useful in detecting heterozygous large deletions. These results expand the spectrum of mutations in the ATP6V0A4 and ATP6V1B1 genes associated with primary dRTA and provide insight into possible structure-function relationships.
Assuntos
Acidose Tubular Renal/genética , Éxons/genética , Mutação/genética , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Família , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemRESUMO
The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98-NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK-NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.
Assuntos
Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 5/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Proteínas de Homeodomínio , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , PrognósticoRESUMO
BACKGROUND: Kasabach-Merritt phenomenon (KMP) is a rare condition and optimal treatments have not yet been established, especially for cases that are unresponsive to first-line therapy. We retrospectively reviewed 11 KMP cases treated over the past 13 years in our institute. OBSERVATIONS: With the exception of 1 case, steroids were administered as the first-line therapy. Eight cases required second-line or third-line therapy. The effective salvage therapies include interferon (n=1), radiotherapy (n=1), and chemotherapy (n=5). One case continues to depend upon chemotherapy. Three refractory cases were therapy dependent over 1 year of age, whereas 8 were treated effectively by 6 months of age. CONCLUSIONS: Chemotherapy seems to be the most effective therapy for steroid-resistant KMP cases.