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 Stonerock; Julie M. Gastier-Foster; Meenakshi Devidas; Yunfeng Dai; Brent Wood; Michael 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 V. 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

doi:10.1038/ncomms13331

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 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 V. 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

Oncology

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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.

Original language	English (US)
Article number	13331
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13331
State	Published - Nov 8 2016

ASJC Scopus subject areas

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

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Gu, Z., Churchman, M., Roberts, K., Li, Y., Liu, Y., Harvey, R. C., McCastlain, K., Reshmi, S. C., Payne-Turner, D., Iacobucci, I., Shao, Y., Chen, I. M., Valentine, M., Pei, D., Mungall, K. L., Mungall, A. J., Ma, Y., Moore, R., Marra, M., ... Mullighan, C. G. (2016). Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nature communications, 7, Article 13331. https://doi.org/10.1038/ncomms13331

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, M, Larsen, EE, Maloney, K, Mattano, LA, Angiolillo, A, Salzer, WL, Burke, MJ, Gianni, F, Spinelli, O, Radich, JP, Minden, MD, Moorman, AV, 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

@article{d51688b64d384b51ae702a1c15e566c8,

title = "Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia",

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.",

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

note = "Funding Information: We thank Haitao Ji for providing BCL9 inhibitors. This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrick's Foundation Scholar Award (to C.G.M.); by a St. Baldrick's Consortium Award (S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex's Lemonade Stand Foundation Young Investigator Awards (K.R.), by an Alex's Lemonade Stand Foundation Award (M.L.) and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and C.G.M.); and grants to the COG: U10 CA98543 (Chair's grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. We thank the staff of the Biorepository, the Hartwell Centre for Bioinformatics and Biotechnology, the Flow Cytometry and Cell Sorting Core Facility and the Cytogenetics Core Facility of St Jude Children's Research Hospital. Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2016",

month = nov,

day = "8",

doi = "10.1038/ncomms13331",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

AU - Gu, Zhaohui

AU - Churchman, Michelle

AU - Roberts, Kathryn

AU - Li, Yongjin

AU - Liu, Yu

AU - Harvey, Richard C.

AU - McCastlain, Kelly

AU - Reshmi, Shalini C.

AU - Payne-Turner, Debbie

AU - Iacobucci, Ilaria

AU - Shao, Ying

AU - Chen, I. Ming

AU - Valentine, Marcus

AU - Pei, Deqing

AU - Mungall, Karen L.

AU - Mungall, Andrew J.

AU - Ma, Yussanne

AU - Moore, Richard

AU - Marra, Marco

AU - Stonerock, Eileen

AU - Gastier-Foster, Julie M.

AU - Devidas, Meenakshi

AU - Dai, Yunfeng

AU - Wood, Brent

AU - Borowitz, Michael

AU - Larsen, Eric E.

AU - Maloney, Kelly

AU - Mattano, Leonard A.

AU - Angiolillo, Anne

AU - Salzer, Wanda L.

AU - Burke, Michael J.

AU - Gianni, Francesca

AU - Spinelli, Orietta

AU - Radich, Jerald P.

AU - Minden, Mark D.

AU - Moorman, Anthony V.

AU - Patel, Bella

AU - Fielding, Adele K.

AU - Rowe, Jacob M.

AU - Luger, Selina M.

AU - Bhatia, Ravi

AU - Aldoss, Ibrahim

AU - Forman, Stephen J.

AU - Kohlschmidt, Jessica

AU - Mrózek, Krzysztof

AU - Marcucci, Guido

AU - Bloomfield, Clara D.

AU - Stock, Wendy

AU - Kornblau, Steven

AU - Kantarjian, Hagop M.

AU - Konopleva, Marina

AU - Paietta, Elisabeth

AU - Willman, Cheryl L.

AU - Loh, Mignon L.

AU - Hunger, Stephen P.

AU - Mullighan, Charles G.

N1 - Funding Information: We thank Haitao Ji for providing BCL9 inhibitors. This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrick's Foundation Scholar Award (to C.G.M.); by a St. Baldrick's Consortium Award (S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex's Lemonade Stand Foundation Young Investigator Awards (K.R.), by an Alex's Lemonade Stand Foundation Award (M.L.) and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and C.G.M.); and grants to the COG: U10 CA98543 (Chair's grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. We thank the staff of the Biorepository, the Hartwell Centre for Bioinformatics and Biotechnology, the Flow Cytometry and Cell Sorting Core Facility and the Cytogenetics Core Facility of St Jude Children's Research Hospital. Publisher Copyright: © The Author(s) 2016.

PY - 2016/11/8

Y1 - 2016/11/8

N2 - 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.

AB - 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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U2 - 10.1038/ncomms13331

DO - 10.1038/ncomms13331

M3 - Article

C2 - 27824051

AN - SCOPUS:84994404372

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 13331

ER -

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

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