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

被引：20

作者：

Padella, Antonella ^{[1
]}

Simonetti, Giorgia ^{[2
]}

Paciello, Giulia ^{[3
]}

Giotopoulos, George ^{[4
,5
,6
]}

Baldazzi, Carmen ^{[7
]}

Righi, Simona ^{[1
]}

Ghetti, Martina ^{[2
]}

Stengel, Anna ^{[8
]}

Guadagnuolo, Viviana ^{[1
]}

De Tommaso, Rossella ^{[1
]}

Papayannidis, Cristina ^{[1
]}

Robustelli, Valentina ^{[1
]}

Franchini, Eugenia ^{[2
]}

di Rora, Andrea Ghelli Luserna ^{[2
]}

Ferrari, Anna ^{[2
]}

Fontana, Maria Chiara ^{[1
]}

Bruno, Samantha ^{[1
]}

Ottaviani, Emanuela ^{[1
]}

Soverini, Simona ^{[1
]}

Storlazzi, Clelia Tiziana ^{[9
]}

Haferlach, Claudia ^{[8
]}

Sabattini, Elena ^{[1
]}

Testoni, Nicoletta ^{[1
]}

Iacobucci, Ilaria ^{[10
]}

Huntly, Brian J. P. ^{[4
,5
,6
]}

Ficarra, Elisa ^{[3
]}

Martinelli, Giovanni ^{[2
]}

机构：

[1] Univ Bologna, Dept Expt Diagnost & Special Med, I-40138 Bologna, Italy

[2] Ist Sci Romagnolo Studio & Cura Tumori IRST IRCCS, I-47014 Meldola, FC, Italy

[3] Politecn Torino, Dept Control & Comp Engn DAUIN, I-10129 Turin, Italy

[4] Univ Cambridge, Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge CB2 1TN, England

[5] Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 0XY, England

[6] Univ Cambridge, Addenbrookes Hosp, Cambridge CB2 0XY, England

[7] St Orsola Malpighi Univ Hosp, Inst Hematol L&A Seragnoli, I-40138 Bologna, Italy

[8] MLL Munich Leukemia Lab, D-81377 Munich, Germany

[9] Univ Bari Aldo Moro, Dept Biol, I-70125 Bari, Italy

[10] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

来源：

CANCERS | 2019年 / 11卷 / 12期

关键词：

acute myeloid leukemia; rare fusion genes; ZEB2-BCL11B; ACUTE LYMPHOBLASTIC-LEUKEMIA; CARBOXYPEPTIDASE-D; CANCER; SUBUNIT; CNOT2; CLASSIFICATION; NUP98-PHF23; REPRESSION; EXPRESSION; PROLACTIN;

D O I：

10.3390/cancers11121951

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：22