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Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia

Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy
Department of Control and Computer Engineering DAUIN, Politecnico di Torino, 10129 Turin, Italy
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1TN, UK
Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0XY, UK
Institute of Hematology “L. and A. Seràgnoli”, Sant’Orsola-Malpighi University Hospital, 40138 Bologna, Italy
MLL-Munich Leukemia Laboratory, 81377 Munich, Germany
Department of Biology, University of Bari Aldo Moro, 70125 Bari, Italy
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Author to whom correspondence should be addressed.
A.P. and G.S. contributed equally to this study.
Cancers 2019, 11(12), 1951;
Received: 16 October 2019 / Revised: 15 November 2019 / Accepted: 2 December 2019 / Published: 5 December 2019
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. View Full-Text
Keywords: acute myeloid leukemia; rare fusion genes; ZEB2-BCL11B acute myeloid leukemia; rare fusion genes; ZEB2-BCL11B
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MDPI and ACS Style

Padella, A.; Simonetti, G.; Paciello, G.; Giotopoulos, G.; Baldazzi, C.; Righi, S.; Ghetti, M.; Stengel, A.; Guadagnuolo, V.; De Tommaso, R.; Papayannidis, C.; Robustelli, V.; Franchini, E.; Ghelli Luserna di Rorà, A.; Ferrari, A.; Fontana, M.C.; Bruno, S.; Ottaviani, E.; Soverini, S.; Storlazzi, C.T.; Haferlach, C.; Sabattini, E.; Testoni, N.; Iacobucci, I.; Huntly, B.J.P.; Ficarra, E.; Martinelli, G. Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia. Cancers 2019, 11, 1951.

AMA Style

Padella A, Simonetti G, Paciello G, Giotopoulos G, Baldazzi C, Righi S, Ghetti M, Stengel A, Guadagnuolo V, De Tommaso R, Papayannidis C, Robustelli V, Franchini E, Ghelli Luserna di Rorà A, Ferrari A, Fontana MC, Bruno S, Ottaviani E, Soverini S, Storlazzi CT, Haferlach C, Sabattini E, Testoni N, Iacobucci I, Huntly BJP, Ficarra E, Martinelli G. Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia. Cancers. 2019; 11(12):1951.

Chicago/Turabian Style

Padella, Antonella, Giorgia Simonetti, Giulia Paciello, George Giotopoulos, Carmen Baldazzi, Simona Righi, Martina Ghetti, Anna Stengel, Viviana Guadagnuolo, Rossella De Tommaso, Cristina Papayannidis, Valentina Robustelli, Eugenia Franchini, Andrea Ghelli Luserna di Rorà, Anna Ferrari, Maria C. Fontana, Samantha Bruno, Emanuela Ottaviani, Simona Soverini, Clelia T. Storlazzi, Claudia Haferlach, Elena Sabattini, Nicoletta Testoni, Ilaria Iacobucci, Brian J.P. Huntly, Elisa Ficarra, and Giovanni Martinelli. 2019. "Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia" Cancers 11, no. 12: 1951.

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