RESUMO
Zinc finger protein 384 (ZNF384) rearrangement defined a novel subtype of B-cell acute lymphoblastic leukemia (B-ALL). The prognostic significance of ZNF384 fusion transcript levels represented measurable residual disease remains to be explored. ZNF384 fusions were screened out in 57 adult B-ALL patients at diagnosis by real-time quantitative polymerase chain reaction and their transcript levels were serially monitored during treatment. The reduction of ZNF384 fusion transcript levels at the time of achieving complete remission had no significant impact on survival, whereas its ≥2.5-log reduction were significantly associated with higher relapse free survival (RFS) and overall survival (OS) rates after course 1 consolidation (p = 0.022 and = 0.0083) and course 2 consolidation (p = 0.0025 and = 0.0008). Compared with chemotherapy alone, allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly improved RFS and OS of patients with <2.5-log reduction after course 1 consolidation (p < 0.0001 and = 0.0002) and course 2 consolidation (p = 0.0003 and = 0.019), whereas exerted no significant effects in patients with ≥2.5-log reduction (all p > 0.05). ZNF384 fusion transcript levels after course 1 and course 2 consolidation strongly predict relapse and survival and may guide whether receiving allo-HSCT in adult B-ALL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Prognóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Fatores de Transcrição , Neoplasia Residual/diagnóstico , Recidiva , Transativadores/metabolismo , Transativadores/uso terapêuticoRESUMO
The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Transativadores , Animais , Humanos , Camundongos , Doxorrubicina , Proteína p300 Associada a E1A , Interleucina-3 , Subunidade alfa de Receptor de Interleucina-3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transativadores/metabolismoRESUMO
Zinc finger protein 384 (ZNF384) encodes a C2H2-type zinc finger protein that can function as a transcription factor. ZNF384 rearrangement in acute lymphoblastic leukemia (ALL) was first reported in 2002. More than 19 different ZNF384 fusion partners have been detected in ALL. These include E1A-binding protein P300 (EP300), CREB-binding protein (CREBBP), transcription factor 3 (TCF3), TATA-box binding protein associated factor 15 (TAF15), Ewing sarcoma breakpoint region 1 gene (EWSR1), AT-rich interactive domain-containing protein 1B (ARID1B), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2), synergin gamma (SYNRG), clathrin heavy chain (CLTC), bone morphogenic protein 2-inducible kinase (BMP2K), Nipped-B-like protein (NIPBL), A Kinase Anchoring Protein 8 (AKAP8), Chromosome 11 Open Reading Frame 74 (C11orf74), DEAD-Box Helicase 42 (DDX42), ATP Synthase F1 Subunit Gamma (ATP2C1), Euchromatic Histone Lysine Methyltransferase 1 (EHMT1), Testic Expressed 41 (TEX41), etc. Patients diagnosed with ALL harboring ZNF384 rearrangements commonly had a good prognosis. The mechanisms, performance, and features of different ZNF384 rearrangements in acute lymphoblastic leukemia have been well evaluated.
Assuntos
Actinas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Cromatina , Proteínas de Ciclo Celular , DNA Helicases , Proteínas Nucleares , Fatores de Transcrição , Transativadores , ATPases Transportadoras de CálcioRESUMO
Glioblastoma (GBM) is a primary tumor in the intracranial compartment. Vasculogenic mimicry (VM) is a process in which a pipeline of tumor cells that provide blood support to carcinogenic cells is formed, and studying VM could provide a new strategy for clinical targeted treatment of GBM. In the present study, we found that SNORD17 and ZNF384 were significantly upregulated and promoted VM in GBM, whereas KAT6B was downregulated and inhibited VM in GBM. RTL-P assays were performed to verify the 2'-O-methylation of KAT6B by SNORD17; IP assays were used to detect the acetylation of ZNF384 by KAT6B. In addition, the binding of ZNF384 to the promoter regions of VEGFR2 and VE-cadherin promoted transcription, as validated by chromatin immunoprecipitation and luciferase reporter assays. And finally, knockdown of SNORD17 and ZNF384 combined with KAT6B overexpression effectively reduced the xenograft tumor size, prolonged the survival time of nude mice and reduced the number of VM channels. This study reveals a novel mechanism of the SNORD17/KAT6B/ZNF384 axis in modulating VM development in GBM that may provide a new goal for the comprehensive treatment of GBM.
Assuntos
Glioblastoma , Animais , Camundongos , Humanos , Glioblastoma/genética , Glioblastoma/tratamento farmacológico , Camundongos Nus , Metilação , Linhagem Celular Tumoral , RNA Mensageiro , Histona Acetiltransferases/uso terapêuticoRESUMO
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has many subtypes with diverse clinical and biological features and outcomes. Next generation sequencing has revealed several novel subtypes, including the ZNF384 and MEF2D rearrangements. The clinical characteristics and outcomes of the largest series of BCP-ALL cases with ZNF384 and MEF2D rearrangements in an international collaborative study are described here. Patients with ZNF384 rearrangements appear to express various leukemic phenotypes, including BCP-ALL (with or without abnormal expression of myeloid markers) and B/myeloid mixed phenotype acute leukemia. We provide strong evidence that among BCP-ALL patients with a ZNF384 fusion, the partner gene is associated with demographic features and influences the outcome; particularly the EP300-ZNF384 fusion is associated with a low risk of relapse. MEF2D rearrangements have been primarily described in children and young adults with BCP-ALL. Previous research has suggested that patients with MEF2D-BCL9 fusion have a high risk of relapse. Despite having the MEF2D-HNRNPUL1 fusion gene, the prognosis was favorable. Improved diagnostic genomic testing will enable future prospective studies to clarify the clinical significance of the ZNF384 and MEF2D rearrangements in childhood and young adult BCP-ALL.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Estudos Prospectivos , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transativadores/genética , Fatores de Transcrição MEF2/genéticaRESUMO
BACKGROUND: Breast cancer has become the most frequently diagnosed cancer worldwide. Increasing evidence indicated that zinc finger proteins (ZNFs), the largest family of transcription factors, contribute to cancer development and progression. Although ZNF384 is overexpressed in several types of human cancer, the role of ZNF384 in breast cancer remains unknown. Therefore, our research focused on ZNF384 regulation of the malignant phenotype of breast cancer and the underlying molecular mechanisms. METHODS: CCK-8 and colony formation assays were used to evaluate cell proliferation. Transwell and scratch assays were used to evaluate the cell migration and invasion. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were used to confirm the target relationship between ZNF384 and zinc finger E-box binding homeobox 1 (ZEB1). Xenografts were used to monitor the targets in vivo effects. RESULTS: We noted that ZNF384 was significantly overexpressed in breast cancer and highlighted the oncogenic mechanism of ZNF384. ZNF384 transactivated ZEB1 expression and induced an epithelial and mesenchymal-like phenotype, resulting in breast cancer metastasis. Furthermore, ZNF384 may be a target of miR-485-5p, and ZEB1 can up-regulate ZNF384 expression by repressing miR-485-5p expression. Together, we unveiled a feedback loop of ZNF384-ZEB1 in breast cancer metastasis. CONCLUSIONS: The findings suggest that ZNF384 can serve as a prognostic factor and a therapeutic target for breast cancer patients.
Assuntos
Neoplasias da Mama , MicroRNAs , Segunda Neoplasia Primária , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Retroalimentação , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma , MicroRNAs/genética , MicroRNAs/metabolismo , Processos Neoplásicos , Neoplasias Cutâneas , Transativadores/genética , Fatores de Transcrição/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Melanoma Maligno CutâneoRESUMO
EP300-ZNF384 fusion is a rare recurrent cytogenetic abnormality associated with B cell acute lymphoblastic leukemia (B-ALL), which was rarely studied in Chinese patient cohort. Here, we used a customized RNA fusion gene panel to investigate gene fusions in 56 selected acute leukemia patients without conventional genetic abnormalities. Two EP300-ZNF384 fusion forms were detected in ten cases, which were in-frame fusions of EP300 exon 6 fused with exon 3 or 2 of ZNF384. The fusions led to the lack of most functional domains of EP300. We firstly reported EP300-ZNF384 fusion in a mixed-phenotype acute leukemia (MPAL) patient whose CD33 and CD13 were negative. The rest nine B-ALL patients with EP300-ZNF384 fusion expressed CD33 and/or CD13. Fifty-six percent of B-ALL patients (5/9) with EP300-ZNF384 fusion were positive with CD10. After the diagnosis of EP300-ZNF384 fusion, 70% of the patients achieved remission after chemotherapy. Our observations indicated that EP300-ZNF384 fusion consists of a distinct subgroup of B-ALL with a characteristic immunophenotype. These patients are sensitive to current chemotherapy regimen and have an excellent outcome.
Assuntos
Proteína p300 Associada a E1A , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , RNA Neoplásico , Análise de Sequência de RNA , Transativadores , Adulto , Estudos de Coortes , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Feminino , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
For a long time, treatment for adult acute lymphoblastic leukemia (ALL) lacked significant improvements. Since 2000, new approaches, such as the treatments of adolescent and young adult ALL using pediatric-like protocols and Ph+ ALL treatments using tyrosine kinase inhibitor-combined chemotherapies. Further improvements are expected from the use of pediatric-like protocols to whole adults, and the use of newly approved anti-cancer drugs, such as inotuzumab ozogamicin and blinatumomab. Furthermore, comprehensive genetic analyses using next generation sequencing technology have recently discovered new recurrent fusion genes of ALL, such as DUX4 fusion genes, ZNF384 fusion genes, and MEF2D fusion genes. In this review, I will introduce these frontline studies and discuss about the treatment of patients with adult ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Fatores de Transcrição , Translocação GenéticaRESUMO
Fusion genes found in cases of acute lymphoblastic leukemia (ALL) are reported to be associated with age, such as MLL rearrangements in neonates and BCR-ABL1 in adults. However, the pathogenesis of ALL in adolescents and young adults (AYA) remains largely unknown. To investigate the potential role of fusion genes, we performed RNA-sequencing on 73 BCR-ABL1-negative ALL patients who were all AYA. Interestingly, DUX4-IGH was the most frequent fusion gene detected in B-ALL (18.5%) and was preferentially detected in the AYA generation. ZNF384 and MEF2D genes were also recurrently identified as functionally relevant fusion genes in 16.7% and 9.3% of AYA with B-ALL, respectively. Patients with DUX4 and ZNF384 fusion genes displayed better prognosis, while those with the MEF2D fusion gene displayed a worse outcome. To improve treatment outcome, the fusion genes detected in this study will be useful for risk stratification and target therapy.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Genoma Humano , Humanos , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto JovemRESUMO
Recent cancer genomics studies have identified mutation patterns characteristic of APOBEC3B (A3B) in multiple cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. A3B expression is upregulated by HPV E6/E7 oncoproteins, implying a crucial role for A3B upregulation in HPV-induced carcinogenesis. Here, we explored the molecular mechanisms underlying the activation of the A3B promoter by E6. Luciferase reporter assays with a series of deleted fragments of the human A3B promoter in normal immortalized human keratinocytes (NIKS) identified two functional regions in the promoter: the distal region (from -200 to -51), which is required for basal promoter activity, and the proximal region (from +1 to +45), which exerts an inhibitory effect on gene expression. Each promoter region was found to contain an E6-responsive element(s). Disruption of an AT-rich motif located between +10 and +16 abrogated the proximal-region-mediated activation of the A3B promoter by E6. DNA pull-down assays revealed that a cellular zinc-finger protein, ZNF384, binds to the AT-rich motif in the A3B promoter, and chromatin immunoprecipitation assays confirmed that ZNF384 binds to the A3B promoter in cells. ZNF384 knockdown reduced the A3B mRNA levels in NIKS expressing E6, but not in the parental NIKS, indicating that ZNF384 contributes to A3B upregulation by E6, but not to basal A3B expression. The exogenous expression of ZNF384 led to the activation of the A3B promoter in NIKS. Collectively, these results indicate that E6 activates the A3B promoter through the distal and proximal regions, and that ZNF384 is required for the proximal-region-mediated activation of A3B.
Assuntos
Citidina Desaminase/genética , Proteínas Oncogênicas Virais/fisiologia , Regiões Promotoras Genéticas , Proteínas Repressoras/fisiologia , Sequência de Bases , Linhagem Celular Transformada , Citidina Desaminase/metabolismo , DNA , Técnicas de Silenciamento de Genes , Humanos , Antígenos de Histocompatibilidade Menor , Dados de Sequência Molecular , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética , Transativadores/metabolismoAssuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteína EWS de Ligação a RNA/genética , Transativadores/genética , Translocação Genética/genética , Aloenxertos , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Proteínas de Fusão Oncogênica , Pediatria , Cromossomo Filadélfia , Resultado do TratamentoRESUMO
BACKGROUND: ZNF384-fusion (Z-fusion) genes were recently identified in B-cell acute lymphoblastic leukemia (B-ALL) and are frequent in Japanese adult patients. The frequency is about 20% in those with Philadelphia chromosome-negative B-ALL. ZNF384 is a transcription factor and Z-fusion proteins have increased transcriptional activity; however, the detailed mechanisms of leukemogenesis of Z-fusion proteins have yet to be clarified. METHODS: We established three transfectants of cell lines expressing different types of Z-fusion proteins, and analyzed their gene expression profile (GEP) by RNA-seq. We also analyzed the GEP of clinical ALL samples using our previous RNA-seq data of 323 Japanese ALL patients. We selected upregulated genes in both Z-fusion gene-expressing transfectants and Z-fusion gene-positive ALL samples, and investigated the binding of Z-fusion proteins to regulatory regions of the candidate genes by ChIP-qPCR. RESULTS: We selected six commonly upregulated genes. After the investigation by ChIP-qPCR, we finally identified CREB5 and RGS1 as direct and common target genes. RGS1 is an inhibitor of CXCL12-CXCR4 signaling that is required for the homing of hematopoietic progenitor cells to the bone marrow microenvironment and development of B cells. Consistent with this, Z-fusion gene transfectants showed impaired migration toward CXCL12. CONCLUSIONS: We identified CREB5 and RGS1 as direct and common transcriptional targets of Z-fusion proteins. The present results provide novel insight into the aberrant transcriptional regulation by Z-fusion proteins.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Proteínas de Fusão Oncogênica , Proteínas RGS , Humanos , Linhagem Celular Tumoral , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação Leucêmica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Proteínas RGS/genética , Proteínas RGS/metabolismo , TransativadoresRESUMO
Glioma remains one of the most challenging primary brain malignancies to treat. Long noncoding RNAs (lncRNAs) and mRNAs (mRNAs) are implicated in regulating the malignant phenotypes of cancers including glioma. This study aimed to elucidate the functions and mechanisms of lncRNA LINC00265 and mRNA IFI30 in the pathogenesis of glioma. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed the upregulated expression of LINC00265 and IFI30 in glioma cells compared to normal human astrocytes. Western blot (WB) quantified the associated proteins. Glioma stemness and epithelial-to-mesenchymal transition (EMT) were assessed by aldehyde dehydrogenase 1 (ALDH1) activity, sphere formation, and WB. Mechanistic and rescue assays evaluated the LINC00265/miR-let-7d-5p/IFI30/ZNF384/IGF2BP2 axis. The results demonstrated that LINC00265 and IFI30 were highly expressed in glioma cells, promoting stemness and EMT. ZNF384 was identified as a transcription factor that upregulates IFI30. Moreover, LINC00265 elevated ZNF384 by sponging miR-let-7d-5p and recruiting IGF2BP2. In conclusion, LINC00265 and IFI30 act as oncogenes in glioma by driving stemness and EMT, underscoring their potential as therapeutic targets.
Assuntos
Neoplasias Encefálicas , Glioma , MicroRNAs , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , RNA não Traduzido/genéticaRESUMO
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous malignancy and consists of several genetic abnormalities. Some of these abnormalities are used in clinics for risk calculation and treatment decisions. Patients with ZNF384 rearrangements had a distinct expression profile regardless of their diagnosis, BCP-ALL or mixed phenotype acute leukemia (MPAL) and defined as a new subtype of ALL. In this study, we screened 42 MPAL and 91 BCP-ALL patients for the most common ZNF384 fusions; ZNF384::TCF3, ZNF384::EP300 and ZNF384::TAF15 by using PCR. We identified ZNF384 fusions in 9.5% of MPAL and 7.6% of BCP-ALL. A novel breakpoint was identified in ZNF384::TCF3 fusion in one BCP-ALL patient. T-myeloid MPAL patients showed significantly lower ZNF384 expression compared to lymphoid groups. Patients with ZNF384r had intermediate survival rates based on other subtypes. Prognostic and patient-specific treatment evaluation of ZNF384 fusions in both ALL and MPAL might help to improve risk characterization of patients.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Transativadores/genética , Transativadores/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Transcrição/genética , Fenótipo , Dedos de ZincoRESUMO
BACKGROUND: ZNF384 rearrangement has been recently identified as a new subtype of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive studies clarifying immunophenotypic features and discriminating them from non-ZNF384 in adult BCP-ALL remain scarce to date. METHODS: Flow cytometric assessments were retrospectively performed in 43 patients with ZNF384 rearrangement, 45 with BCR-ABL1, 29 with KMT2A rearrangement and 44 with other BCP-ALL in the analysis cohort. RESULTS: CD33- and CD13-positive frequencies were significantly higher in patients with ZNF384 rearrangement than in those with non-ZNF384; however, no significant difference was observed in CD10- and CD123-positive frequencies. Analysis of antigen-positive cell proportion and median fluorescence intensity (MFI) further indicated that patients with ZNF384 rearrangement had significantly lower CD10 and higher CD33, CD13, and CD123 proportion and MFI. However, compared with KMT2A rearrangement, the CD10 expression in patients with ZNF384 rearrangement was higher, with the median percentage and MFI of 36.16 (3.63-94.79)% versus 4.53 (0.03-21.00)%, and 4.50 (0.86-32.26) versus 2.06 (0.87-4.04), respectively (p < 0.0001). Furthermore, compared with BCR-ABL1 and other BCP-ALL, ZNF384 rearrangement had significantly higher CD33 and CD13 proportion and MFI (p < 0.0001 and p < 0.05, respectively). In addition, higher CD123 proportion and MFI in ZNF384 rearrangement than those in the other three groups were reported for the first time (p < 0.01). A flow cytometry scoring system, including CD10%, CD33MFI, CD13%, and CD123MFI, was proposed and verified to predict ZNF384 rearrangement with high sensitivity and specificity, that is, 76.74% and 91.53% in the analysis and 87.50% and 91.30% in the validation cohort. CONCLUSIONS: The multiparameter immunophenotypic scoring system could suggest ZNF384 rearrangement.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Aberrações Cromossômicas , Citometria de Fluxo , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-3 , Neprilisina , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Estudos Retrospectivos , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Novel fusion genes such as ZNF384, have been identified in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in recent years. Patients harboring ZNF384 rearrangements have a distinctive immunophenotype with weak CD10 and aberrant CD13 and/or CD33 expression. Thus, ZNF384-rearranged ALL is a unique subtype of BCP-ALL. However, research on the prognostic significance of ZNF384 rearrangements has been limited to date, especially in adolescents. CASE PRESENTATION: We described a 17-year-old adolescent who was diagnosed with ALL and had renal involvement as the first manifestation, which was very rare in the existing studies. FISH analysis indicated a rearrangement of ZNF384 according to its probe. The patient had a typical characteristic immunophenotype of ZNF384 rearrangement, with CD10 negativity and CD13 and CD33 positivity. She had an unfavorable prognosis because she responded poorly to chemotherapy and developed a relapse shortly after reaching CR. CONCLUSION: The importance of ZNF384 rearrangements in terms of prognosis remains unclear. We reported an adolescent who was diagnosed with ZNF384-rearranged ALL with renal involvement. She underwent different therapies, but her prognosis remained poor. Since ZNF384 rearrangements may act as a prognostic predictor in children or adolescents, early detection based on its characteristic immunophenotype is of great necessity.
RESUMO
Previous studies have shown that, the clinical features and prognosis of ZNF384-rearranged pediatric acute lymphoblastic leukemia (ALL) depend on its translocation partners. We report two cases of TCF4-ZNF384 fusion, one 6-year-old girl and one 10-year-old boy, both diagnosed by whole-transcriptome sequencing, and TCF4 is the newest fusion partner of ZNF384. As illustrated in this first report of TCF4-ZNF384 fusion in ALL patients, the identification of patients with ZNF384 rearrangement in ALL patients is critical to elucidate outcomes associated with a specific rearrangement and to develop appropriate treatment strategies. In addition, the development of other methods to detect ZNF384 specific translocation partners and leukemia specific targeting agents is of great significance to further improve the prognosis of ALL with ZNF384-rearrangement.
RESUMO
B-cell acute lymphoblastic leukemia (B-ALL) is a malignant tumor originating from B-lineage lymphoid precursor cells. The incidence of B-ALL is about 80% in childhood acute leukemia and 20% in adults. In recent years, with standardized treatment guided by risk stratification, the long-term disease-free survival rate of children is about 80%, while that of adults is less than 40%. However, the specific pathogenesis of the newly identified B-ALL and the targeted therapy strategies have not been vigorously investigated. In this review, we highlight the recent breakthroughs in mechanistic studies and novel therapeutic options in DUX4- and MEF2D-subtype B-ALLs.
RESUMO
HCC has remained one of the challenging cancers to treat, owing to the paucity of drugs targeting the critical survival pathways. Considering the cancer cells are deficient in DNase activity, the increase of an autonomous apoptisis endonuclease should be a reasonable choice for cancer treatment. In this study, we investigated whether DNASE1L3, an endonuclease implicated in apoptosis, could inhibit the progress of HCC. We found DNASE1L3 was down-regulated in HCC tissues, whereas its high expression was positively associated with the favorable prognosis of patients with HCC. Besides, serum DNASE1L3 levels were lower in HCC patients than in healthy individuals. Functionally, we found that DNASE1L3 inhibited the proliferation of tumor cells by inducing G0/G1 cell cycle arrest and cell apoptosis in vitro. Additionally, DNASE1L3 overexpression suppressed tumor growth in vivo. Furthermore, we found that DNASE1L3 overexpression weakened glycolysis in HCC cells and tissues via inactivating the rate-limiting enzymes involved in PTPN2-HK2 and CEBPß-p53-PFK1 pathways. Finally, we identified the HBx to inhibit DNASE1L3 expression by up-regulating the expression of ZNF384. Collectively, our findings demonstrated that DNASE1L3 could inhibit the HCC progression through inducing cell apoptosis and weakening glycolysis. We believe DNASE1L3 could be considered as a promising prognostic biomarker and therapeutic target for HCC.
Assuntos
Apoptose , Carcinoma Hepatocelular/metabolismo , Desoxirribonucleases/metabolismo , Glicólise , Neoplasias Hepáticas/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Xenoenxertos , Hexoquinase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfofrutoquinase-1/metabolismoRESUMO
INTRODUCTION: Aeromonads are gram-negative opportunistic bacteria, mainly found in aquatic environments. Hematologic patients are particularly at risk of Aeromonas soft tissue infections and septicemia, especially during chemotherapy-induced neutropenia. CASE DESCRIPTION: A 46-year-old man was diagnosed with acute lymphoblastic leukemia characterized by the rare t(12;17)(p13;q21)/TAF15-ZNF384 aberration. On day 22 of chemotherapy, he developed febrile neutropenia followed by necrotizing fasciitis in his upper right extremity. Despite appropriate antibiotic therapy and prompt surgical intervention, he died within 36 h after the appearance of a fever. A multi-sensitive Aeromonas hydrophila was isolated from all cultural sites. DISCUSSION AND CONCLUSIONS: In a previous paper we characterized the patient's aberration with cytogenetic and FISH analysis. Here, we provide details regarding the patient's rapidly progressing infection and underline the importance of maintaining high clinical suspicion of Aeromonas infections in acute leukemia. Given the unusually rapid progression of an infection caused by a rare non-resistant pathogen, and after considering data on the implication of metalloproteinase function in immune system regulation, a correlation between risk of severe infection and TAF15-ZNF384 aberrated acute lymphoblastic leukemia cannot be ruled out.