Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes ( BCL9 , CSF1R , DAZAP1 , HNRNPUL1 and SS18 ) in 22 B progenitor ALL (B-ALL) cases...

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Veröffentlicht in:	Nature communications Jg. 7; H. 1; S. 13331 - 10
Hauptverfasser:	Gu, Zhaohui, Churchman, Michelle, Roberts, Kathryn, Li, Yongjin, Liu, Yu, Harvey, Richard C., McCastlain, Kelly, Reshmi, Shalini C., Payne-Turner, Debbie, Iacobucci, Ilaria, Shao, Ying, Chen, I-Ming, Valentine, Marcus, Pei, Deqing, Mungall, Karen L., Mungall, Andrew J., Ma, Yussanne, Moore, Richard, Marra, Marco, Stonerock, Eileen, Gastier-Foster, Julie M., Devidas, Meenakshi, Dai, Yunfeng, Wood, Brent, Borowitz, Michael, Larsen, Eric E., Maloney, Kelly, Mattano Jr, Leonard A., Angiolillo, Anne, Salzer, Wanda L., Burke, Michael J., Gianni, Francesca, Spinelli, Orietta, Radich, Jerald P., Minden, Mark D., Moorman, Anthony V., Patel, Bella, Fielding, Adele K., Rowe, Jacob M., Luger, Selina M., Bhatia, Ravi, Aldoss, Ibrahim, Forman, Stephen J., Kohlschmidt, Jessica, Mrózek, Krzysztof, Marcucci, Guido, Bloomfield, Clara D., Stock, Wendy, Kornblau, Steven, Kantarjian, Hagop M., Konopleva, Marina, Paietta, Elisabeth, Willman, Cheryl L., L. Loh, Mignon, P. Hunger, Stephen, Mullighan, Charles G.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 08.11.2016 Nature Publishing Group Nature Portfolio
Schlagworte:	13/1 13/106 13/31 13/44 14/32 38/39 38/91 631/67/69 64/60 692/308/2056 692/699/67/1990/283/2125 82/1 Animals Base Sequence Cancer research Gene Expression Regulation, Leukemic Gene Rearrangement - genetics Genomics - methods Hematology Histone Deacetylase Inhibitors - pharmacology Hospitals Humanities and Social Sciences Humans Kinases Leukemia Luciferases - metabolism Medical research Medicine MEF2 Transcription Factors - genetics Mice multidisciplinary NIH 3T3 Cells Oncogene Proteins, Fusion - genetics Oncology Pathology Pediatrics Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Science Science (multidisciplinary) Sequence Analysis, RNA Transcriptome Treatment Outcome Canada San Francisco California United Kingdom > UK New Mexico United States > US Maine Tennessee Ohio California Maryland Pennsylvania
ISSN:	2041-1723, 2041-1723
Online-Zugang:	Volltext
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Zusammenfassung:	Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes ( BCL9 , CSF1R , DAZAP1 , HNRNPUL1 and SS18 ) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9 . Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2 ; thus, MEF2D- rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D- rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D- rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered. Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D , which lead to increased transcriptional activity of the gene, and cellular transformation in vitro .
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms13331