Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

McClure, Barbara J.; Heatley, Sue L.; Kok, Chung Hoow; Sadras, Teresa; An, Jiyuan; Hughes, Timothy P.; Lock, Richard B.; Yeung, David T.; Sutton, Rosemary; White, Deborah L.

doi:10.1038/s41416-018-0022-0

Cited by 32 publications

(47 citation statements)

References 16 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other detected fusions may provide prognostic information (P2RY8-CRLF2, MEF2D-BCL9) [25][26][27]. Many fusion transcripts have already been described in pediatric ALL (e.g., HOOK3-FGFR1, PAX5-DACH1, EP300-ZNF384, PAX5-ETV6, or ZNF618-NUTM1), even though their potential therapeutic or prognostic impact remains to be addressed in more detail [28][29][30][31][32][33]. To the best of our knowledge, some fusions identified in this study have not been described in the literature yet.…”

Section: Discussionmentioning

confidence: 99%

Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia

et al. 2020

View full text Add to dashboard Cite

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1 plus profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (n = 1), ETV6-RUNX1 (n = 25), and rearrangements involving KMT2A (n = 3) or TCF3 (n = 3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1 plus (n = 6/12) and Bother (n = 19/36) cases but not in cases with hyperdiploid karyotypes (n = 35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6.

show abstract

Section: Discussionmentioning

confidence: 99%

Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Gocho et al [16] first found EP300-ZNF384 fusion in two samples out of 55 selected pediatric Philadelphia chromosome-negative precursor B acute lymphoblastic leukemia (BCP-ALL) patients without conventional genetic abnormalities. The frequencies of EP300-ZNF384 fusion are 1.3% (2/152) in children and 5.7% (7/122) in adolescent/young adult (AYA)/adult of BCR-ABL1-negative pre-B-ALL patients [19]. The frequencies of total ZNF384-fusion genes in BCP-ALL are 4-8% in children [6,8] and 7% in adults [8], and 17% in adolescents and young adults (15-24 years old) [9].…”

Section: Discussionmentioning

confidence: 99%

Detection of EP300-ZNF384 fusion in patients with acute lymphoblastic leukemia using RNA fusion gene panel sequencing

Jing

Wan³

et al. 2020

Ann Hematol

View full text Add to dashboard Cite

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.

show abstract

“…ZNF384 r-ALL represents 1% to 5% of BCP-ALL and 5% to 10% of B-others. The unique gene expression signature of this ALL subtype is enriched for hematopoietic stem cell and immature myeloid lineage features and reflects upregulation of the JAK-STAT signaling pathway 30 , 31 . ZNF384 r-ALL also frequently displays a distinct immunophenotype compared with the majority of other BCP-ALL subtypes; the immunophenotypically distinct ZNF384 r-ALL cases do not express (or only weakly express) CD10 marker but express myeloid markers CD13 or CD33 (or both) and may be even classified as mixed-phenotype acute leukemias on the basis of EGIL (European Group for the Immunological Characterization of Leukaemias) or WHO criteria 30 , 32 – 34 .…”

Section: New Bcp-all Subtypesmentioning

confidence: 99%

New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia

2018

View full text Add to dashboard Cite

Traditionally, genetic abnormalities detected by conventional karyotyping, fluorescence in situ hybridization, and polymerase chain reaction divided childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) into well-established genetic subtypes. This genetic classification has been prognostically relevant and thus used for the risk stratification of therapy. Recently, the introduction of genome-wide approaches, including massive parallel sequencing methods (whole-genome, -exome, and -transcriptome sequencing), enabled extensive genomic studies which, together with gene expression profiling, largely expanded our understanding of leukemia pathogenesis and its heterogeneity. Novel BCP-ALL subtypes have been described. Exact identification of recurrent genetic alterations and their combinations facilitates more precise risk stratification of patients. Discovery of targetable lesions in subsets of patients enables the introduction of new treatment modalities into clinical practice and stimulates the transfer of modern methods from research laboratories to routine practice.

show abstract

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

Abstract: Importantly, this report contributes to a better overview of the incidence of EP300-ZNF384 patients and show that they have a distinct gene signature with concurrent up-regulation of JAK-STAT pathway, reduced expression of B-cell regulators and reduced DNA repair capacity.

Cited by 32 publications

References 16 publications

Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia

Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia

Detection of EP300-ZNF384 fusion in patients with acute lymphoblastic leukemia using RNA fusion gene panel sequencing

New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia

Contact Info

Product

Resources

About