ABSTRACT
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3-PBX1 fusions, ETV6-RUNX1-positive/ETV6-RUNX1-like, DUX4 fusions, ZNF384 fusions, BCR-ABL1/Ph-like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH-CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4-HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/classification , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Transcriptome , Adult , Child , Databases, Nucleic Acid , Female , Humans , Male , Models, Genetic , Mutation , Oncogene Fusion , Oncogene Proteins, Fusion/genetics , Prognosis , Sequence Analysis, RNAABSTRACT
OBJECTIVE: To study the clinical effect of the SCMC APL-2010 regimen in the treatment of acute promyelocytic leukemia (APL) in children. METHODS: A retrospective analysis was performed for the clinical data of 44 children with APL who received treatment with the SCMC APL-2010 regimen between April 2010 and July 2016. The Kaplan-Meier survival analysis was used to evaluate event-free survival (EFS) rate and overall survival (OS) rate. RESULTS: Of the 44 children with APL, 42 (95%) achieved a complete remission (CR) after one course of treatment and 1 achieved CR after two courses of treatment, with an overall CR rate of 98%. The 9-year EFS and OS rates were 96%±3% and 97.7%±2.2% respectively. As for adverse events, 41 (93%) had infection, 29 (66%) had granulocyte reduction, 12 (27%, 1 died) had differentiation syndrome, 16 (36%) had liver dysfunction, 12 (27%) had adverse gastrointestinal reactions, and 7 (16%) had QT prolongation, 1 (2%) had orchitis, and no secondary neoplasm was observed. CONCLUSIONS: Children with APL receiving the SCMC APL-2010 regimen have a good prognosis and can achieve a long-term survival, while treatment-related infection is commonly seen.
Subject(s)
Leukemia, Promyelocytic, Acute , Antineoplastic Combined Chemotherapy Protocols , Child , Disease-Free Survival , Humans , Male , Remission Induction , Retrospective Studies , Treatment Outcome , TretinoinABSTRACT
Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Mercaptopurine/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Humans , Mercaptopurine/metabolism , Methyltransferases/genetics , Pharmacogenetics , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Pyrophosphatases/geneticsABSTRACT
HYPB is a human histone H3 lysine 36 (H3K36)-specific methyltransferase and acts as the ortholog of yeast Set2. This study explored the physiological function of mammalian HYPB using knockout mice. Homozygous disruption of Hypb impaired H3K36 trimethylation but not mono- or dimethylation, and resulted in embryonic lethality at E10.5-E11.5. Severe vascular defects were observed in the Hypb(-/-) embryo, yolk sac, and placenta. The abnormally dilated capillaries in mutant embryos and yolk sacs could not be remodeled into large blood vessels or intricate networks, and the aberrantly rounded mesodermal cells exhibited weakened interaction with endothelial cells. The embryonic vessels failed to invade the labyrinthine layer of placenta, which impaired the embryonic-maternal vascular connection. These defects could not be rescued by wild-type tetraploid blastocysts, excluding the possibility that they were caused by the extraembryonic tissues. Consistent with these phenotypes, gene expression profiling in wild-type and Hypb(-/-) yolk sacs revealed that the Hypb disruption altered the expression of some genes involved in vascular remodeling. At the cellular level, Hypb(-/-) embryonic stem cell-derived embryonic bodies, as well as in vitro-cultured human endothelial cells with siRNA-mediated suppression of HYPB, showed obvious defects in cell migration and invasion during vessel formation, suggesting an intrinsic role of Hypb in vascular development. Taken together, these results indicate that Hypb is required for embryonic vascular remodeling and provide a tool to study the function of H3K36 methylation in vasculogenesis/angiogenesis.
Subject(s)
Embryo, Mammalian/physiology , Gene Expression Regulation, Developmental/physiology , Histone-Lysine N-Methyltransferase/metabolism , Neovascularization, Physiologic/physiology , Animals , Cells, Cultured , Embryo, Mammalian/metabolism , Gene Expression Profiling , Histone-Lysine N-Methyltransferase/genetics , Humans , Methylation , Mice , Mice, Knockout , Neovascularization, Physiologic/genetics , RNA InterferenceABSTRACT
Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (â¼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).
Subject(s)
Leukemia, Myeloid, Acute , Leukemia, Promyelocytic, Acute , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Promyelocytic, Acute/genetics , Tretinoin , HLA-DR Antigens , Arsenic TrioxideABSTRACT
OBJECTIVE: To reduce the risk of therapy related complication during the treatment and keeps the long term event free survival, and to evaluate the results and risk factors of SCMC-lymphoblastic leukemia (ALL)-2005 protocol. METHODS: Designed the new protocol SCMC-ALL-2005 based on the previous protocol XH-99 for ALL. Divided the patients into low, median and high risk groups depends on risk factors including day 33 and 55 minimal residual disease (MRD) level. The higher risk group, the more intensive therapy was given. All the cases were registed on pediatric oncology network database (POND). All the abandonment patients were counted as event. From May 1(st) 2005 to April 30(th) 2009, 351 children who were newly diagnosed as B lineage ALL were enrolled in this study. The prognoses relating to risk grouping, age, mutation gene and MRD level were analyzed. RESULTS: Up to June 30, 2011, 273 patients were followed up with median time 49 months (range 26 to 74 months). Three hundred and forty-five patients (98.29%) achieved complete remission on day 35 induction. 12 cases were younger than 1 year old (3.42%), 285 cases between 1 and 9 years old (81.20%), 54 cases 10 to 18 years old (15.38%). Five year event-free survival (EFS) was 34%, 72% and 63%, respectively. One hundred and fifty-six cases belonged to lowered risk (44.44%), 177 to middle risk (50.43%) and 18 to higher risk (5.13%). Five year EFS was 78%, 64% and 30%, respectively. In this study, 18 patients were detected positive for BCR/ABL, 3 for MLL/AF4, 16 for PBX/E2A, and 36 for TEL/AML. The 5 year EFS were 11%, 66%, 75% and 74%, respectively. A total of 300 cases were tested for MRD levels on day 35. Of them, 241 cases were with MRD ≤ 0.01% (negative), and 59 cases > 0.01% (positive). The 5 year relapse free survival (RFS) was 79% and 58%, respectively. Total 6 patients died of complication (1.71%). 18 patients were abundant treatment with no disease progress. 70 patients relapsed (19.94%), including 52 bone marrow, 8 central nerve system (CNS), 1 both in bone marrow and CNS, 1 second cancer (M(4)) and 8 testis. Five year overall survival (OS) and EFS are 84% and 69%. CONCLUSIONS: The risk of therapy related death is low with the protocol SCMC-ALL-2005. MRD affects the prognosis. The long term prognosis is poor for high risk group, with BCR/ABL and positive MRD.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Burkitt Lymphoma/therapy , Neoplasm, Residual/therapy , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Prospective StudiesABSTRACT
OBJECTIVE: Cytogenetic abnormalities have been proven to be the most valuable parameter for risk stratification of childhood acute lymphoblastic leukemia (ALL). However, studies on the prevalence of cytogenetic abnormalities and their correlation to clinical features in Chinese pediatric patients are limited, especially large-scale studies. METHODS: We collected the cytogenetics and clinical data of 1541 children newly diagnosed with ALL between 2001 and 2014 in four Chinese hospitals, and retrospectively analyzed their clinical features, prognosis and risk factors associated with pediatric ALL. RESULTS: All of these patients had karyotyping results, and some of them were tested for fusion genes by fluorescence in situ hybridization or reverse-transcription polymerase chain reaction. Overall, 930 cases (60.4%) had abnormal cytogenetics in this study, mainly including high hyperdiploidy (HHD, n=276, 17.9%), hypodiploidy (n=74, 4.8%), t(12;21)/TEL-AML1 (n=260, 16.9%), t(1;19)/E2A-PBX1 (n=72, 4.7%), t(9;22)/BCR-ABL (n=64, 4.2%), and t(v;11q23)/MLL rearrangements (n=40, 2.6%). The distribution of each cytogenetic abnormality was correlated with gender, age, white blood cell count at diagnosis, and immunophenotype. In addition, multivariate analysis suggested that t(v;11q23)/MLL rearrangements (OR: 2.317, 95%CI: 1.219-3.748, P=0.008) and t(9;22)/BCR-ABL (OR: 2.519, 95%CI: 1.59-3.992, P<0.001) were independent risk factors for a lower event-free survival (EFS) rate in children with ALL, while HHD (OR: 0.638, 95%CI: 0.455-0.894, P=0.009) and t(12;21)/TEL-AML1 (OR: 0.486, 95%CI: 0.333-0.707, P<0.001) were independent factors of a favorable EFS. CONCLUSION: The cytogenetic characteristics presented in our study resembled other research groups, emphasizing the important role of cytogenetic and molecular genetic classification in ALL, especially in B-ALL.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Child , Child, Preschool , China/epidemiology , Cytogenetic Analysis , Female , Humans , Infant , Male , Retrospective StudiesABSTRACT
RIG-I has been implicated in innate immunity by sensing intracellular viral RNAs and inducing type I IFN production. However, we have found a significant RIG-I induction in a biological setting without active viral infection-namely, during RA-induced terminal granulocytic differentiation of acute myeloid leukemias. Here, we present evidence that a significant Rig-I induction also occurs during normal myelopoiesis and that the disruption of the Rig-I gene in mice leads to the development of a progressive myeloproliferative disorder. The initiation of progressive myeloproliferative disorder is mainly due to an intrinsic defect of Rig-I(-/-) myeloid cells, which are characterized by a reduced expression of IFN consensus sequence binding protein, a major regulator of myeloid differentiation. Thus, our study reveals a critical regulatory role of Rig-I in modulating the generation and differentiation of granulocytes.
Subject(s)
DEAD-box RNA Helicases/physiology , Gene Expression Regulation , Granulocytes/cytology , Receptors, Retinoic Acid/physiology , Animals , Cell Differentiation , Cell Proliferation , DEAD Box Protein 58 , Exons , Granulocytes/metabolism , Hematopoietic Stem Cells/cytology , Humans , Immunity, Innate , Mice , Mice, Knockout , Mice, Transgenic , Myeloid Cells/cytology , Myeloproliferative Disorders/metabolismABSTRACT
OBJECTIVE: This study quantitatively examined signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels in peripheral blood of children with acute lymphoblastic leukemia (ALL) at different stages in order to evaluate the role of sjTRECs in predicting severe infection postchemotherapy. METHODS: sjTRECs levels in peripheral blood were measured by fluorescent quantitation-polymerase chain reaction in 30 children with newly diagnosed ALL, 36 children with ALL who accepted chemotherapy but were not infected, 30 children with ALL who had severe infection after chemotherapy, and 50 normal children. RESULTS: Blood sjTRECs levels in the normal group (394 ± 270 copies/103 MNC) were significantly higher than those in the other three groups (P<0.05). Blood sjTRECs levels in the chemotherapy group without infection (96 ± 78 copies/103 MNC) were significantly lower than those in the newly diagnosed ALL group (210 ± 219 copies/103 MNC) (P<0.05). The chemotherapy group with severe infection showed the lowest blood sjTRECs levels (48 ± 40 copies/103 MNC) in the four groups. CONCLUSIONS: The measurement of blood sjTRECs levels might be helpful for predicting the occurrence of severe infection postchemotherapy in children with ALL.
Subject(s)
DNA, Circular/blood , Gene Rearrangement, T-Lymphocyte , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunologyABSTRACT
RATIONALE: Relapsed or refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, showing survival rates of less than a year even with the use of novel therapies. In this report, we describe the safe and effective use of trametinib combined with dasatinib in a patient with acute lymphoblastic leukemia (ALL). To the best of our knowledge, this is the first report on the successful use of 2 targeted drugs such as trametinib and dasatinib in a pediatric patient with Ph+ ALL and recurrent pancreatitis. PATIENT CONCERNS: A 6-year-old boy with ALL and Philadelphia chromosome (Ph+) who had recurrent asparaginase-associated pancreatitis. DIAGNOSIS: The patient was diagnosed with ALL, based on clinical features, laboratory analyses, bone marrow aspiration evaluation in morphology, immunology, cytogenetics, and molecular. INTERVENTIONS: The patient was treated with dasatinib combined with an intermediate risk-oriented chemotherapy. However, owing to recurrent asparaginase-associated pancreatitis, the patient has to abandon asparaginase in consolidation. Considering the high risk of relapse, we used trametinib and dasatinib combined with chemotherapy as maintenance chemotherapy. OUTCOMES: After 6 months, there were no obvious side effects or residual disease. LESSONS: We suggest that the combination of trametinib and dasatinib may represent a viable option to treat patients with potential relapsed/refractory Ph+ ALL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Dasatinib/administration & dosage , Pancreatitis/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asparaginase/administration & dosage , Asparaginase/adverse effects , Azathioprine/administration & dosage , Azathioprine/adverse effects , Child , Consolidation Chemotherapy/methods , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Dasatinib/adverse effects , Humans , Maintenance Chemotherapy/methods , Male , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Pyridones/adverse effects , Pyrimidinones/adverse effects , Treatment OutcomeABSTRACT
PURPOSE: Myopia and its extreme form, high myopia, are common vision disorders worldwide, especially in Asia. Identifying genetic markers is a useful step toward understanding the genetic basis of high myopia, particularly in the Chinese population, where it is highly prevalent. This study was conducted to provide evidence of linkage for autosomal dominant high myopia to a locus on chromosome 5p13.3-p15.1 in a large Chinese family. METHODS: After clinical evaluation, genomic DNA from 29 members of this family was genotyped. A genome-wide screen was then performed using 382 markers with an average inter-marker distance of 10 cM, and two-point linkage was analyzed using the MLINK program. Mutation analysis of the candidate genes was performed using direct sequencing. RESULTS: Linkage to the known autosomal dominant high myopia loci was excluded. The genome-wide screening identified a maximum two-point LOD score of 3.71 at θ=0.00 with the microsatellite marker D5S502. Fine mapping and haplotype analysis defined a critical region of 11.69 cM between D5S2096 and D5S1986 on chromosome 5p13.3-p15.1. Sequence analysis of the candidate genes inside the linked region did not identify any causative mutations. CONCLUSIONS: A genetic locus was mapped to chromosome 5p13.3-p15.1 in a large Chinese family with autosomal dominant high myopia.
Subject(s)
Asian People/genetics , Chromosomes, Human, Pair 5/genetics , Genes, Dominant/genetics , Genetic Loci/genetics , Myopia/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , China , DNA Mutational Analysis , Family , Female , Genetic Linkage , Genetic Markers , Haplotypes/genetics , Humans , Male , Middle Aged , Pedigree , Young AdultABSTRACT
OBJECTIVE: To understand the nature of subjective memory complaints through comparative study of depression status of patients with subjective memory complaints and mild cognitive impairment. METHODS: A total of 214 patients were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale, the Geriatric Depression Scale and some neuropsychological tests. Among them, 76 were of subjective memory complaints (SMC), 74 amnestic mild cognitive impairment-single domain (aMCI-s) and 64 amnestic mild cognitive impairment-multiple domain (aMCI-m). RESULTS: According to CESD, 31% of the patients had symptoms of depression. The ratios were 30%, 24% and 39% in SMC, aMCI-s and aMCI-m groups respectively. GDS study showed that 43% of the patients had symptoms of depression. The ratios were 47%, 30% and 53% in SMC, aMCI-s and aMCI-m groups respectively. The ratio in SMC group fell between the other two groups. The total score of CESD (12 +/- 10) or GDS (11 +/- 6) of the SMC group, reflecting the severity of depression, fell between aMCI-s (CESD: 11 +/- 8, GDS: 9 +/- 5) and (CESD: 15 +/- 11, GDS: 12 +/- 7) groups. There was no significant difference between them in comparison with either aMCI-s or aMCI-m group (P > 0.05). But the total score of CESD or GDS was significantly different between aMCI-m and aMCI-s groups (P < 0.05). The depression status was worse in aMCI-m group than that in aMCI-s group. CONCLUSION: There is no significant discrepancy in the incidence and severity of depression between SMC and aMCI groups. It indicates that depressive mood is not the specific cause of SMC.
Subject(s)
Cognition Disorders , Depressive Disorder/psychology , Memory Disorders , Aged , Aged, 80 and over , Cognition Disorders/diagnosis , Depressive Disorder/diagnosis , Female , Humans , Male , Memory Disorders/diagnosis , Middle AgedABSTRACT
OBJECTIVE: To evaluate the long-term outcomes of childhood stage III neuroblastoma (NB) and its associated prognostic factors. METHODS: Children with newly diagnosed NB were enrolled into the protocol of NB-99 and followed up from January 1999 to May 2007. The relevant data were collected. And the statistics was processed by SPSS 10.0. RESULTS: Thirty children with stage III NB were found among all 101 children with NB. There were 19 males and 11 females. The mean age at diagnosis was (33 +/- 30) months. Abdomen and thorax were by far the most common sites of primary tumor (16 and 10 respectively). Twenty-one NB children had favorable pathology classification. Eleven NB children were treated according to the mediate-risk protocol, 6 children received autologous stem cell transplantation (ASCT) after chemotherapy and 5 patients had no therapy of cis-retinoic acid. Follow-up was conducted for 5 - 96 months. A complete response or an excellent partial remission was observed in 28 patients. Seven patients relapsed or progressed at the primary tumor site or bone marrow. The estimated cumulative probabilities of event-free survival and overall survival at 4 years for these 30 patients were 74% +/- 9% and 77% +/- 8% respectively. On univariate analysis, pathological type, high levels of LDH and ferritin, non-therapy of cis-retinoic acid were associated with a worse survival (chi2 = 9.48, 6.82, 9.17, 9.06, all P < 0.05). As to the multivariate estimates of hazards ratio, high levels of LDH and ferritin, no ASCT and non-therapy of cis-retinoic acid were associated with a worse survival (OR = 3.95, 3.44, 2.64, 1.27, all P < 0.05). CONCLUSION: Stage III NB children with favorable histologic features, normal LDH, normal serum ferritin, receive ASCT, and treated with cis-retinoic acid have a lower risk of relapse.
Subject(s)
Neuroblastoma/drug therapy , Neuroblastoma/pathology , Child, Preschool , Combined Modality Therapy , Female , Humans , Infant , Male , Neoplasm Staging , Neuroblastoma/diagnosis , Prognosis , Retrospective Studies , Treatment OutcomeABSTRACT
Inspired by biological neural systems, neuromorphic devices may lead to new computing paradigms for exploring cognition, learning and limits of parallel computation. Synapses form the basis of neuromorphic computing and have attracted significant research interest in recent years. Herein, a three-terminal transistor based on a transition metal sulfide and zinc oxide heterojunction is proposed for emulating biological synapses. The transistor exhibits an ON/OFF ratio (104) and significant rectifying behavior with forward-to-reverse bias current ratios of 104. The device demonstrates the essential synaptic behaviors, such as excitatory postsynaptic current, modulation of synaptic weight and paired-pulse facilitation. Furthermore, we show that the hysteretic effect of the transfer curves and the post-synapse current triggered by the presynaptic pulses can be modulated by illumination, and the current under illumination conditions is about 10 times greater than that in the dark. These synapses combine photonic with electric neuromorphic functions, thus showing the application prospects of the optoelectronic interfaces for integrated photonic circuits based on mixed-mode electro-optical operation. Hence, this work offers a new landscape for 2D-material electronics and encourages future research on neuro-electronics.
ABSTRACT
Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q22;q21), resulting in a PML-RARA fusion that is the master driver of APL. A few cases that cannot be identified with PML-RARA by using conventional methods (karyotype analysis, FISH, and RT-PCR) involve abnormal promyelocytes that are fully in accordance with APL in morphology, cytochemistry, and immunophenotype. To explore the mechanisms involved in pathogenesis and recurrence of morphologically diagnosed APL, we performed comprehensive variant analysis by next-generation sequencing in 111 pediatric patients morphologically diagnosed as APL. Structural variant (SV) analysis in 120 DNA samples from both diagnosis and relapse stage identified 95 samples with RARA rearrangement (including 94 with PML-RARA and one with NPM-RARA) and two samples with KMT2A rearrangement. In the eligible 13 RNA samples without any RARA rearrangement at diagnosis, one case each with CPSF6-RARG, NPM1-CCDC28A, and TBC1D15-RAB21 and two cases with a TBL1XR1-RARB fusion were discovered. These uncovered fusion genes strongly suggested their contributions to leukemogenesis as driver alternations and APL phenotype may arise by abnormalities of other members of the nuclear receptor superfamily involved in retinoid signaling (RARB or RARG) or even by mechanisms distinct from the formation of aberrant retinoid receptors. Single-nucleotide variant (SNV) analysis in 77 children (80 samples) with RARA rearrangement showed recurrent alternations of primary APL in FLT3, WT1, USP9X, NRAS, and ARID1A, with a strong potential for involvement in pathogenesis, and WT1 as the only recurrently mutated gene in relapsed APL. WT1, NPM1, NRAS, FLT3, and NSD1 were identified as recurrently mutated in 17 primary samples without RARA rearrangement and WT1, NPM1, TP53, and RARA as recurrently mutated in 9 relapsed samples. The survival of APL with RARA rearrangement is much better than without RARA rearrangement. Thus, patients morphologically diagnosed as APL that cannot be identified as having a RARA rearrangement are more reasonably classified as a subclass of AML other than APL, and individualized treatment should be considered according to the genetic abnormalities.
Subject(s)
Biomarkers, Tumor/genetics , Granulocyte Precursor Cells/pathology , Leukemia, Promyelocytic, Acute/genetics , Mutation , Neoplasm Recurrence, Local/genetics , Oncogene Proteins, Fusion/genetics , Translocation, Genetic , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Case-Control Studies , Child , Child, Preschool , Female , Follow-Up Studies , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Granulocyte Precursor Cells/metabolism , Humans , Infant , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Male , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/drug therapy , Nucleophosmin , Prognosis , Retrospective Studies , Survival RateABSTRACT
Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Signal Transduction/drug effects , Animals , Antineoplastic Agents , Cell Line, Tumor , Child , Cytokines/metabolism , Drug Resistance, Neoplasm/drug effects , Female , Gene Expression Regulation, Leukemic/drug effects , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , TNF Receptor-Associated Factor 6/metabolismABSTRACT
BACKGROUND: Familial pulmonary arterial hypertension (FPAH) is an autosomal dominant disorder characterized by plexiform lesions of endothelial cells in pulmonary arterioles which leads to elevated pulmonary arterial pressure, right-sided heart failure and death. Heterozygous mutations in the bone morphogenetic protein type II receptor gene (BMPR2) have been found to underlie a majority of FPAH cases. More than 140 distinct mutations have been identified in FPAH cases and in idiopathic pulmonary arterial hypertension (IPAH) cases, but only one mutation has been reported in Chinese patients. METHODS: A three-generation pedigree of FPAH and another 10 patients with IPAH were collected. In the family, two of the 9 surviving and one deceased family member were diagnosed as FPAH. The entire protein-coding region and intron/exon boundaries of the BMPR2 gene were amplified by PCR using DNA samples from affected individuals. Direct sequencing of PCR products was performed on both the sense and antisense strands. To confirm the segregation of the mutation within the family and exclude the presence of the mutation in normal subjects, the relevant exon was amplified by PCR, followed by mutation-specific RPLP analysis. RESULTS: In the Chinese pedigree with FPAH an A-to-T transition at position 1157 in exon 9 of the BMPR2 gene was identified which resulted in a Glu386Val mutation. We confirmed the segregation of the mutation within the family and excluded the presence of the mutation in a panel of 200 chromosomes from normal subjects. No mutation was detected in BMPR2 in the other 10 patients with IPAH. CONCLUSIONS: This amino acid substitution occurs at a glutamic acid that is highly conserved in all type II TGF-beta receptors. The nearly invariant Glu forms an ion pair with an invariant Arg at position 491 thereby helping to stabilize the large lobe. Substitution of Arg at position 491 is the most frequently observed missense mutation in FPAH, but until now no mutations at position 386 have been found in FPAH. The predicted functional impact of the Glu386Val mutation and its absence in healthy controls support the mutation as the cause of FPAH.
Subject(s)
Bone Morphogenetic Protein Receptors, Type II/genetics , Hypertension, Pulmonary/genetics , Mutation , Adolescent , Amino Acid Sequence , Child , Child, Preschool , Female , Humans , Infant , Male , Molecular Sequence Data , PedigreeABSTRACT
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.
Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Leukemic , Genomics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Transcriptome , Adolescent , Adult , Aged , Bone Marrow/pathology , Child , Child, Preschool , Cluster Analysis , DNA Copy Number Variations , Genomics/methods , High-Throughput Nucleotide Sequencing , Humans , Infant , Middle Aged , Mutation , Mutation Rate , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Young AdultABSTRACT
BACKGROUND: The clinical management of children with renal tumors including Wilms' tumor, clear cell sarcoma, rhabdoid tumor and other renal tumors in our center was designed according to the National Wilms' Tumor Study Group protocols. METHODS: A total of 142 consecutive patients who had been diagnosed as having renal tumors at Shanghai Children's Medical Center were reviewed retrospectively in the period of December 1998 and September 2012. Diagnosis and treatment were decided by a multidisciplinary team including oncologists, surgeons, pathologists and sub-specialized radiologists. RESULTS: The median age of the patients at the time of diagnosis was 27 months. The tumor stages of the patients were as follows: stage I 24.6%, stage II 23.2%, stage III 32.3%, stage IV 14.1%, and stage V 5.6%. Favorable histology was diagnosed in 80.3%, anaplasia in 4.2%, clear cell sarcoma in 9.8%, rhabdoid tumor in 4.9%, and other renal tumors in 0.7% of the patients. The event-free and overall 5-year survival rates were 80% and 83%, respectively. Tumor relapse and progress was seen in 25 patients (17.6%). The median relapse time was 6 months (range: 2-37 months). Seven relapsing patients were retreated and four of them got second complete remission (three in stage II, one in stage I). CONCLUSION: A multi-disciplinary team work model is feasible in developing countries, and the renal tumors protocols basically from developed countries are safe in developing countries.