scholarly journals The Prognostic Significance of ZNF384 Fusions in Adult Ph-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: A Comprehensive Cohort Study From a Single Chinese Center

2021 ◽  
Vol 11 ◽  
Author(s):  
Ya-Zhen Qin ◽  
Qian Jiang ◽  
Lan-Ping Xu ◽  
Yu Wang ◽  
Hao Jiang ◽  
...  
Keyword(s):  
Cohort Study ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Large Scale ◽  
Zinc Finger Protein ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Fusion Transcript ◽  
Cell Precursor

Novel recurrent fusion gene types such as zinc finger protein 384 (ZNF384) fusions have been identified in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the application of next-generation sequencing technologies. However, the comprehensive large-scale clinical cohort study for clarifying their prognostic significance remains scarce to date. A total of 242 consecutive adult Ph-negative BCP-ALL patients treated in our institute were retrospectively screened ZNF384 fusions at diagnosis by multiplex real time quantitative PCR. ZNF384 fusions were identified in 47 patients (19.4%) and all belonged to B-other ALL (having no high hyperdiploid karyotype, BCR-ABL1, TCF3-PBX1, ETV6-RUNX1, or MLL rearrangement). In the whole cohort, patients with ZNF384 fusions had significantly higher 3-year relapse-free-survival (RFS) and tended to have a higher 3-year overall survival (OS) than those with no ZNF384 fusions (80.1% vs. 52.5%, P = 0.013; 67.6% vs. 54.0%, P = 0.10). For patients receiving chemotherapy alone and received allogeneic-hematologic stem cell transplantation (allo-HSCT) were censored at the time of transplantation, patients with ZNF384 fusions had both similar RFS and similar OS to B-other ALL patients with no ZNF384 fusions (RFS: P =0.94 and 0.30; OS: P =0.94 and 0.51). For patients receiving transplantation, those with ZNF384 fusions had significantly higher 3-year RFS than B-other ALL patients with no ZNF384 fusions and their OS were similar (P = 0.022 and 0.24). Only two of 31 patients with ZNF384 fusions and receiving allo-HSCT relapsed, individually occurred 66.8 and 69.8 months after transplantation. Therefore, ZNF384 fusion is common in adult BCP-ALL, which may define a new group from BCP-ALL containing no classical fusion transcript with better prognosis through receiving allo-HSCT.

scholarly journals NUTM1 is a recurrent fusion gene partner in B-cell precursor acute lymphoblastic leukemia associated with increased expression of genes on chromosome band 10p12.31-12.2

Haematologica ◽  
2019 ◽  
Vol 104 (10) ◽  
pp. e455-e459 ◽  
Author(s):  
Femke M. Hormann ◽  
Alex Q. Hoogkamer ◽  
H. Berna Beverloo ◽  
Aurélie Boeree ◽  
Ilse Dingjan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Chromosome Band ◽  
Cell Precursor ◽  
Expression Of Genes

scholarly journals Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3302-3304 ◽  
Author(s):  
Sima Jeha ◽  
Frederick Behm ◽  
Deqing Pei ◽  
John T. Sandlund ◽  
Raul C. Ribeiro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Cd20 Expression ◽  
Therapy Studies

Abstract CD20 expression is associated with inferior survival in adults with acute lymphoblastic leukemia (ALL). We analyzed the prognostic impact of CD20 expression in 353 children with B-cell precursor ALL treated in 3 consecutive St Jude Total Therapy studies. CD20 expression (> 20%) was found in 169 patients (48%) and was more frequent in patients between 1 and 10 years of age than in those younger than 1 or older than 10 years (P = .001). None of 14 patients with MLL-AF4 expressed CD20. There was no association between CD20 expression and E2A-PBX, TEL-AML1, ploidy, white blood cell count at diagnosis, or sex. In contrast to the experience in adult ALL, our patients with CD20 expression tended to have a better treatment outcome than those without the expression: 5-year event-free survival 84% ± 2.9% versus 78% ± 3.1% (P = .08). These data suggest that CD20 expression is not associated with inferior outcome in pediatric patients treated with contemporary regimens.

scholarly journals PAX5-AUTS2: A recurrent fusion gene in childhood B-cell precursor acute lymphoblastic leukemia

2012 ◽  
Vol 36 (8) ◽  
pp. e178-e181 ◽  
Author(s):  
Dagmar Denk ◽  
Karin Nebral ◽  
Jutta Bradtke ◽  
Gertrud Pass ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor

scholarly journals Modeling the evolution of ETV6-RUNX1–induced B-cell precursor acute lymphoblastic leukemia in mice

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1041-1051 ◽  
Author(s):  
Louise van der Weyden ◽  
George Giotopoulos ◽  
Alistair G. Rust ◽  
Louise S. Matheson ◽  
Frederik W. van Delft ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mouse Model ◽  
B Cell ◽  
Insertional Mutagenesis ◽  
Fusion Gene ◽  
Single Nucleotide Polymorphism Array ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Sleeping Beauty ◽  
Cell Precursor

Abstract The t(12;21) translocation that generates the ETV6-RUNX1 (TEL-AML1) fusion gene, is the most common chromosomal rearrangement in childhood cancer and is exclusively associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The translocation arises in utero and is necessary but insufficient for the development of leukemia. Single-nucleotide polymorphism array analysis of ETV6-RUNX1 patient samples has identified multiple additional genetic alterations; however, the role of these lesions in leukemogenesis remains undetermined. Moreover, murine models of ETV6-RUNX1 ALL that faithfully recapitulate the human disease are lacking. To identify novel genes that cooperate with ETV6-RUNX1 in leukemogenesis, we generated a mouse model that uses the endogenous Etv6 locus to coexpress the Etv6-RUNX1 fusion and Sleeping Beauty transposase. An insertional mutagenesis screen was performed by intercrossing these mice with those carrying a Sleeping Beauty transposon array. In contrast to previous models, a substantial proportion (20%) of the offspring developed BCP-ALL. Isolation of the transposon insertion sites identified genes known to be associated with BCP-ALL, including Ebf1 and Epor, in addition to other novel candidates. This is the first mouse model of ETV6-RUNX1 to develop BCP-ALL and provides important insight into the cooperating genetic alterations in ETV6-RUNX1 leukemia.

scholarly journals Novel MEIS1-FOXO1 Fusion Gene in a Case of Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5283-5283
Author(s):  
Chuang Jiang ◽  
Jiabi Qian ◽  
Wenge Hao ◽  
Wei LIU ◽  
Shuhong Shen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Functional Study ◽  
Cell Precursor ◽  
Foxo1 Gene

Abstract Background: Thanks to the total therapy and systemic basic-translation research, the overall survival rate in children with acute lymphoblastic leukemia (ALL) has dramatically improved to almost 90% over these past few decades. FOXO1 gene belongs to the forkhead family of transcription factors, which play roles in myogenic growth and differentiation. Translocation of FOXO1 with PAX3 has been reported in pediatric alveolar rhabdomyosarcoma. In B-cell precursor ALL, two cases with FOXO1 fusions have been identified already, while its function on ALL remains unknown. Here, we report a novel MEIS1-FOXO1 fusion gene in a case with B-ALL. Methods: Flowcytometery, karyotype, RT-PCR and fluorescence in were employed, MEIS1-FOXO1 was identified as novel fusion gene in a case of pediatric BCP-ALL. Using IL-3 dependent BaF3 cells as study model to test the leukemia transformation potential of MEIS1-FOXO1. Results: A novel MEIS1-FOXO1 fusion was identified in one cease of pediatric B-ALL. Panel next generation sequencing (NGS) showed that the leukemia clone had concurrent NRASG12D, TP53R273H, WHSC1E1099K, ABCC1R1166X, PHGR1H37P, HOXA3P219L and DSTP4606L somatic mutation. This patient was enrolled in CCCG-ALL2015 clinical trial (ChiCTR-IPR-14005706) and achieved completed remission and low minimal residual disease (MRD) level (MRD<0.01%) at day 19 from induction therapy. Functional study showed that MEIS1-FOXO1 fusion gene can potentiate BaF3 cells growth independent of IL3 supplement, as compared to those without MEIS1-FOXO1 fusion transduction. In the meanwhile, we have found that MEIS1-FOXO1 fusion gene can drive cells into S-phase with concurrent decreased G0/G1 phase, which might be its oncogenic role in leukemogenesis. Using qPCR methods, we have found that MEIS1-FOXO1 fusion gene altered the cell cycle related genes expression. Conclusions: Integrating the FOXO1-fusion reports, our data have added more evidence to underline the role of FOXO1 deregulation in the pathogenesis of acute lymphoblastic leukemia. Novel fusion of MEIS1-FOXO1 can potentiate B-ALL via cell cycle entry. Detailed mechanisms involved into the MEIS1-FOXO1 should be further investigated. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Single-Cell Phospho-Profiling in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia Reveals Signaling Differences in Cytogenetic and Prognostic Subgroups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2653-2653
Author(s):  
Manon Queudeville ◽  
Sarah M. Eckhoff ◽  
Klaus-Michael Debatin ◽  
Lueder H. Meyer
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Single Cell ◽  
Poor Prognosis ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Cytogenetic Aberrations

Abstract Abstract 2653 Poster Board II-629 Oncogenesis and tumor progression are supported by alterations in cellular signaling. We used phospho-specific antibodies in combination with surface staining in flow cytometry to analyze specific signaling profiles of leukemia cells at a single cell level. We anayzed 22 xenograft samples derived from NOD/SCID-mice transplanted with primary pediatric B- cell precursor acute lymphoblastic leukemia (BCP- ALL) cells. The cells were isolated from the spleens of leukemia bearing mice and stimulated ex vivo in vitro with different stimulants and cytokines. Activation of various phosphoepitopes was analyzed by flow cytometry and compared to the basal state of unstimulated samples. TEL/AML1 fusion and MLL-rearrangements are the most common cytogenetic aberrations in childhood BCP- ALL and are associated with a good or very poor prognosis, respectively. Although there were no differences detectable in basal phosphorylation between the different cytogenetic subgroups, TEL/AML1- positive samples (n= 5) displayed a significantly lower phosphorylation of extracellular regulated kinase (ERK1/2) after stimulation with PMA (Phorbol-12-myristat-13-acetate, activator of protein kinase C) or interleukin 7 (IL-7), while they showed a significantly higher activation of p38 after stimulation with PMA, compared to samples without translocation (n= 13). Additionally, the fusion gene negative samples showed a downregulation of STAT1-phosphorylation after stimulation with interleukin 10 (IL-10) whereas the TEL/AML1-positive samples showed no change. Interestingly, the MLL- positive samples (n= 3) also did not show a difference in STAT1-phosphorylation after IL-10, but showed significantly stronger STAT1 activation in response to interferon alpha (IFN-a) compared to samples without fusion genes. Moreover, the MLL- positive samples also displayed a weaker reaction in ERK-phosphorylation after IL-7 compared to the leukemia samples without cytogenetic aberrations. Differences in other prognostic subgroups analysed include a weaker phosphorylation of p38 and JNK after anisomycin in samples where the patient initially presented with hyperleucocytosis (> 100.000 WBC/μl) (n= 3), an indicator of poor prognosis. A decrease in STAT3- activation after IL-10 was observed in samples where the patients displayed bone marrow remission on day 15 of therapy (n= 8), compared to no change in the samples of patients with > 5% residual blasts (n= 8), indicative of therapy resistance, at this timepoint. Similar to the results for the cytogenetic subgroups, there were no differences detectable at basal phosphorylation levels between the prognostic subgroups. Taken together, these data show that basal phosphorylation states of specific signaling molecules do not discriminate between the different prognostic subgroups of BCP- ALL analyzed. Cytogenetic and other prognostic subgroups however display specific profiles of signaling networks after stimulation. This strategy will prove helpful to identify mechanisms by which different subgroups with distinct clinical outcomes interpret environmental signals and hereby define pathways important for continued survival, proliferation and resistance eventually leading to novel biomarkers and targeted therapies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals DNMT3A Low-Expression is Correlated to Poor Prognosis in Childhood B Cell Precursor Acute Lymphoblastic Leukemia and Confers Resistance to Daunorubicin on Leukemic Cells

2021 ◽  
Author(s):  
Weijing Li ◽  
Shuguang Liu ◽  
Chanjuan Wang ◽  
Lei Cui ◽  
Xiaoxi Zhao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cell Line ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Leukemic Cells ◽  
Cell Precursor ◽  
Knock Out ◽  
Low Expression

Abstract Background Little is known about DNMT3A expression and its prognostic significance in childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL). MethodsWe determined DNMT3A mRNA expression in 102 children with BCP-ALL. Correlations with relapse-free survival (RFS) and common clinical characteristics were analyzed. DNMT3A was stably knocked out by CRISPR/Cas9 gene editing technology in 697 cell line. Cell proliferation activity after treated with daunorubicin was determined by CCK8 assay in DNMT3A KO 697 cell line.Results DNMT3A expression in BCP-ALL patients who were in CCR was higher than in those who got relapse (P=0.0111). Receiver operating characteristic curve showed prognostic significance of DNMT3A expression (P=0.003). Low expression of DNMT3A (<0.197) was significantly correlated with poor RFS (P<0.001) in children with BCP-ALL. Knock-out of DNMT3A in 697 cell line significantly increased IC50 of daunorubicin (P=0.0057), indicating elevated resistance to daunorubicin. ConclusionsLow expression of DNMT3A associates with poor prognosis in children with BCP-ALL. Knock-out of DNMT3A confers resistance to daunorubicin on leukemic cells.

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