Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

Zhaohui Gu, Michelle Churchman, Kathryn Roberts, Yongjin Li, Yu Liu, Richard C. Harvey, Kelly McCastlain, Shalini C. Reshmi, Debbie Payne-Turner, Ilaria Iacobucci, Ying Shao, I. Ming Chen, Marcus Valentine, Deqing Pei, Karen L. Mungall, Andrew J. Mungall, Yussanne Ma, Richard Moore, Marco Marra, Eileen StonerockJulie M. Gastier-Foster, Meenakshi Devidas, Yunfeng Dai, Brent Wood, Michael J Borowitz, Eric E. Larsen, Kelly Maloney, Leonard A. Mattano, Anne Angiolillo, Wanda L. Salzer, Michael J. Burke, Francesca Gianni, Orietta Spinelli, Jerald P. Radich, Mark D. Minden, Anthony Moorman, Bella Patel, Adele K. Fielding, Jacob M. Rowe, Selina M. Luger, Ravi Bhatia, Ibrahim Aldoss, Stephen J. Forman, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D. Bloomfield, Wendy Stock, Steven Kornblau, Hagop M. Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L. Willman, Mignon L. Loh, Stephen P. Hunger, Charles G. Mullighan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number13331
JournalNature Communications
Volume7
DOIs
StatePublished - Nov 8 2016

Fingerprint

MEF2 Transcription Factors
muscle cells
leukemias
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Fusion reactions
fusion
RNA Sequence Analysis
Histone Deacetylase Inhibitors
sequencing
gene expression
Transcriptome
Gene expression
genes
inhibitors
Leukemia
deoxyribonucleic acid
Genes
examination
Chemical activation
activation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Gu, Z., Churchman, M., Roberts, K., Li, Y., Liu, Y., Harvey, R. C., ... Mullighan, C. G. (2016). Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nature Communications, 7, [13331]. https://doi.org/10.1038/ncomms13331

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. / 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 J; Larsen, Eric E.; Maloney, Kelly; Mattano, Leonard A.; Angiolillo, Anne; Salzer, Wanda L.; Burke, Michael J.; Gianni, Francesca; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Moorman, Anthony; 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.; Loh, Mignon L.; Hunger, Stephen P.; Mullighan, Charles G.

In: Nature Communications, Vol. 7, 13331, 08.11.2016.

Research output: Contribution to journalArticle

Gu, Z, Churchman, M, Roberts, K, Li, Y, Liu, Y, Harvey, RC, McCastlain, K, Reshmi, SC, Payne-Turner, D, Iacobucci, I, Shao, Y, Chen, IM, Valentine, M, Pei, D, Mungall, KL, Mungall, AJ, Ma, Y, Moore, R, Marra, M, Stonerock, E, Gastier-Foster, JM, Devidas, M, Dai, Y, Wood, B, Borowitz, MJ, Larsen, EE, Maloney, K, Mattano, LA, Angiolillo, A, Salzer, WL, Burke, MJ, Gianni, F, Spinelli, O, Radich, JP, Minden, MD, Moorman, A, Patel, B, Fielding, AK, Rowe, JM, Luger, SM, Bhatia, R, Aldoss, I, Forman, SJ, Kohlschmidt, J, Mrózek, K, Marcucci, G, Bloomfield, CD, Stock, W, Kornblau, S, Kantarjian, HM, Konopleva, M, Paietta, E, Willman, CL, Loh, ML, Hunger, SP & Mullighan, CG 2016, 'Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia', Nature Communications, vol. 7, 13331. https://doi.org/10.1038/ncomms13331
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 J ; Larsen, Eric E. ; Maloney, Kelly ; Mattano, Leonard A. ; Angiolillo, Anne ; Salzer, Wanda L. ; Burke, Michael J. ; Gianni, Francesca ; Spinelli, Orietta ; Radich, Jerald P. ; Minden, Mark D. ; Moorman, Anthony ; 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. ; Loh, Mignon L. ; Hunger, Stephen P. ; Mullighan, Charles G. / Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. In: Nature Communications. 2016 ; Vol. 7.
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abstract = "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.",
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