Abstract
Approximately 18% of acute myeloid leukemia (AML) cases express a fusion transcript. However, few fusions are recurrent across AML and the identification of these rare chimeras is of interest to characterize AML patients. Here, we studied the transcriptome of 8 adult AML patients with poorly described chromosomal translocation(s), with the aim of identifying novel and rare fusion transcripts. We integrated RNA-sequencing data with multiple approaches including computational analysis, Sanger sequencing, fluorescence in situ hybridization and in vitro studies to assess the oncogenic potential of the ZEB2-BCL11B chimera. We detected 7 different fusions with partner genes involving transcription factors (OAZ-MAFK, ZEB2-BCL11B), tumor suppressors (SAV1-GYPB, PUF60-TYW1, CNOT2-WT1) and rearrangements associated with the loss of NF1 (CPD-PXT1, UTP6-CRLF3). Notably, ZEB2-BCL11B rearrangements co-occurred with FLT3 mutations and were associated with a poorly differentiated or mixed phenotype leukemia. Although the fusion alone did not transform murine c-Kit+ bone marrow cells, 45.4% of 14q32 non-rearranged AML cases were also BCL11B-positive, suggesting a more general and complex mechanism of leukemogenesis associated with BCL11B expression. Overall, by combining different approaches, we described rare fusion events contributing to the complexity of AML and we linked the expression of some chimeras to genomic alterations hitting known genes in AML.
Highlights
Fusion genes represent a major criterion of diagnosis and prognostic risk stratification in the European Leukemia Net 2017 classification of acute myeloid leukemia (AML) [1], where approximately 18% of cases are characterized by the presence of a known fusion genes as the main driver event [2].The chromosomal translocation t(15;17), leads to the expression of a PML-RARA chimera and characterizes patients with acute promyelocytic leukemia, who generally have favourable prognosis.AMLs expressing the transcripts RUNX1-RUNXT1 and CBFβ-MYH11, associate with the t(8;21) and inv(16), respectively, are known to confer a favourable prognosis
We found that ZEB2-BCL11B and OAZ1-MAFK fusions were previously annotated in two AML
To identify the transcriptional signature associated with BCL11B expression in AML, we studied the gene expression profile (GEP) data of patients
Summary
Fusion genes represent a major criterion of diagnosis and prognostic risk stratification in the European Leukemia Net 2017 classification of AML [1], where approximately 18% of cases are characterized by the presence of a known fusion genes as the main driver event [2].The chromosomal translocation t(15;17), leads to the expression of a PML-RARA chimera and characterizes patients with acute promyelocytic leukemia, who generally have favourable prognosis.AMLs expressing the transcripts RUNX1-RUNXT1 and CBFβ-MYH11, associate with the t(8;21) and inv(16), respectively, are known to confer a favourable prognosis. Fusion genes represent a major criterion of diagnosis and prognostic risk stratification in the European Leukemia Net 2017 classification of AML [1], where approximately 18% of cases are characterized by the presence of a known fusion genes as the main driver event [2]. The chromosomal translocation t(15;17), leads to the expression of a PML-RARA chimera and characterizes patients with acute promyelocytic leukemia, who generally have favourable prognosis. AMLs expressing the transcripts RUNX1-RUNXT1 and CBFβ-MYH11, associate with the t(8;21) and inv(16), respectively, are known to confer a favourable prognosis. The t(6;9), inv(3)/t(3;3), t(v;11q23.3) and t(9;22) abnormalities result in the expression of DEK-NUP214, GATA2/MECOM fusions, KMT2A-fusions and BCR-ABL1, respectively, all of which correlate with a poor outcome [1]. The paradigm is BCR-ABL1 in chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (ALL), which drives leukemogenesis and can be targeted by a specific therapy capable of reversing the leukemic phenotype [3,4]
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