Dataset Information

Systematic application of fluorescence in situ hybridization and immunophenotype profile for the identification of ZNF384 gene rearrangements in B cell acute lymphoblastic leukemia.

ABSTRACT:

Introduction

ZNF384 gene fusions resulting from translocations with several partner genes have been described in B cell acute lymphoblastic leukemia (B-ALL) with a characteristic immunophenotype (aberrant CD13 and or CD33 with dim CD10). The prognosis of patients with this rearrangement appears to depend on the fusion partner. ZNF384 rearrangements have been identified by high through put technologies such as RNA sequencing in most of the studies published. We tested the feasibility of using the characteristic immunophenotype as a tool to screen for patients with ZNF384 translocations which can be subsequently confirmed by cytogenetic / molecular methodologies.

Methods

ZNF384 rearrangements in B-ALL patients at diagnosis with CD10 <80% and were negative for the BCR-ABL1 fusion (n = 109) were identified by fluorescence in situ hybridization followed by confirmation by reverse transcriptase-polymerase chain reaction and Sanger sequencing. The end of induction measurable residual disease evaluated by flow cytometry for these patients was obtained from patient records.

Results

ZNF384 translocations were identified in 14 patients and were cytogenetically cryptic in 13. EP300-ZNF384 was the most common fusion partner (n = 12), while TAF15-ZNF384 and TCF3-ZNF384 were identified in 1 patient each. End of induction MRD by flow cytometry was positive in 5 of 8 patients with the EP300-ZNF384 fusion treated at our center.

Conclusion

Our findings show a practical approach for the identification of ZNF384 gene rearrangements by widely available technologies and indicate that the response to therapy may be heterogeneous even in this subset, which has been reported as having a favorable prognosis.

SUBMITTER: Janet NB

PROVIDER: S-EPMC7611455 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Molecular lesions in T-cell acute lymphoblastic leukemias affect regulators of cell cycle, proliferation, differentiation, survival and apoptosis in multi-step pathogenic pathways. Full genetic characterization is needed to identify events concurring in the development of these leukemias. DESIGN AND METHODS: We designed a combined interphase fluorescence in situ hybridization strategy to study 25 oncogenes/tumor suppressor genes in T-cell acute lymphoblastic leukemias and applied it in 23 adult patients for whom immunophenotyping, karyotyping, molecular studies, and gene expression profiling data were available. The results were confirmed and integrated with those of multiplex-polymerase chain reaction analysis and gene expression profiling in another 129 adults with T-cell acute lymphoblastic leukemias. RESULTS: The combined hybridization was abnormal in 21/23 patients (91%), and revealed multiple genomic changes in 13 (56%). It found abnormalities known to be associated with T-cell acute lymphoblastic leukemias, i.e. CDKN2A-B/9p21 and GRIK2/6q16 deletions, TCR and TLX3 rearrangements, SIL-TAL1, CALM-AF10, MLL-translocations, del(17)(q12)/NF1 and other cryptic genomic imbalances, i.e. 9q34, 11p, 12p, and 17q11 duplication, del(5)(q35), del(7)(q34), del(9)(q34), del(12)(p13), and del(14)(q11). It revealed new cytogenetic mechanisms for TCRB-driven oncogene activation and C-MYB duplication. In two cases with cryptic del(9)(q34), fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction detected the TAF_INUP214 fusion and gene expression profiling identified a signature characterized by HOXA and NUP214 upregulation and TAF_I, FNBP1, C9orf78, and USP20 down-regulation. Multiplex-polymerase chain reaction analysis and gene expression profiling of 129 further cases found five additional cases of TAF_I-NUP214-positive T-cell acute lymphoblastic leukemia. CONCLUSIONS: Our combined interphase fluorescence in situ hybridization strategy greatly improved the detection of genetic abnormalities in adult T-cell acute lymphoblastic leukemias. It identified new tumor suppressor genes/oncogenes involved in leukemogenesis and highlighted concurrent involvement of genes. The estimated incidence of TAF_I-NUP214, a new recurrent fusion in adult T-cell acute lymphoblastic leukemias, was 4.6% (7/152).