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

Research output: Contribution to journal › Article › peer-review

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
Pages (from-to)	13331
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13331
Publication status	Published - 8 Nov 2016

Keywords

Animals
Base Sequence
Gene Expression Regulation, Leukemic
Gene Rearrangement/genetics
Genomics/methods
Histone Deacetylase Inhibitors/pharmacology
Humans
Luciferases/metabolism
MEF2 Transcription Factors/genetics
Mice
NIH 3T3 Cells
Oncogene Proteins, Fusion/genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
Sequence Analysis, RNA
Transcriptome
Treatment Outcome

Access to Document

10.1038/ncomms13331

Cite this

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, 13331. https://doi.org/10.1038/ncomms13331

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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.",

keywords = "Animals, Base Sequence, Gene Expression Regulation, Leukemic, Gene Rearrangement/genetics, Genomics/methods, Histone Deacetylase Inhibitors/pharmacology, Humans, Luciferases/metabolism, MEF2 Transcription Factors/genetics, Mice, NIH 3T3 Cells, Oncogene Proteins, Fusion/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics, Sequence Analysis, RNA, Transcriptome, Treatment Outcome",

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 I-Ming Chen 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}",

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Gu, Z, Churchman, M, Roberts, K, Li, Y, Liu, Y, Harvey, RC, McCastlain, K, Reshmi, SC, Payne-Turner, D, Iacobucci, I, Shao, Y, Chen, I-M, 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, pp. 13331. https://doi.org/10.1038/ncomms13331

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

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.

KW - Animals

KW - Base Sequence

KW - Gene Expression Regulation, Leukemic

KW - Gene Rearrangement/genetics

KW - Genomics/methods

KW - Histone Deacetylase Inhibitors/pharmacology

KW - Humans

KW - Luciferases/metabolism

KW - MEF2 Transcription Factors/genetics

KW - Mice

KW - NIH 3T3 Cells

KW - Oncogene Proteins, Fusion/genetics

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics

KW - Sequence Analysis, RNA

KW - Transcriptome

KW - Treatment Outcome

U2 - 10.1038/ncomms13331

DO - 10.1038/ncomms13331

M3 - Article

C2 - 27824051

SN - 2041-1723

VL - 7

SP - 13331

JO - Nature Communications

JF - Nature Communications

ER -