Genomic Analyses Identify Recurrent MEF2D Fusions in Acute Lymphoblastic Leukemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukemia (ALL). Here, using RNA-sequencing (RNAseq) 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 1164 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 inhibitors treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukemia, for which new therapeutic approaches should be considered.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 14 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001002692	DATA FILES FOR MULLIGHAN MEF2D RNASEQ STRANDED	Illumina HiSeq 2000	200
EGAD00001002704	DATA FILES FOR MULLIGHAN MEF2D RNASEQ UNSTRANDED	Illumina HiSeq 2000	217

Publications	Citations
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. 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. Nat Commun 7: 2016 13331	150
Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group. Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H, Chen IM, Valentine M, Liu Y, Li Y, Shao Y, Easton J, Payne-Turner D, Gu Z, Tran TH, Nguyen JV, Devidas M, Dai Y, Heerema NA, Carroll AJ, Raetz EA, Borowitz MJ, Wood BL, Angiolillo AL, Burke MJ, Salzer WL, Zweidler-McKay PA, Rabin KR, Carroll WL, Zhang J, Loh ML, Mullighan CG, Willman CL, Gastier-Foster JM, Hunger SP. Blood 129: 2017 3352-3361	131
Aberrant splicing in B-cell acute lymphoblastic leukemia. Black KL, Naqvi AS, Asnani M, Hayer KE, Yang SY, Gillespie E, Bagashev A, Pillai V, Tasian SK, Gazzara MR, Carroll M, Taylor D, Lynch KW, Barash Y, Thomas-Tikhonenko A. Nucleic Acids Res 46: 2018 11357-11369	34
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Li JF, Dai YT, Lilljebjörn H, Shen SH, Cui BW, Bai L, Liu YF, Qian MX, Kubota Y, Kiyoi H, Matsumura I, Miyazaki Y, Olsson L, Tan AM, Ariffin H, Chen J, Takita J, Yasuda T, Mano H, Johansson B, Yang JJ, Yeoh AE, Hayakawa F, Chen Z, Pui CH, Fioretos T, Chen SJ, Huang JY. Proc Natl Acad Sci U S A 115: 2018 E11711-E11720	146
PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, Hagiwara K, Pelletier S, Gingras S, Berns H, Payne-Turner D, Hill A, Iacobucci I, Shi L, Pounds S, Cheng C, Pei D, Qu C, Newman S, Devidas M, Dai Y, Reshmi SC, Gastier-Foster J, Raetz EA, Borowitz MJ, Wood BL, Carroll WL, Zweidler-McKay PA, Rabin KR, Mattano LA, Maloney KW, Rambaldi A, Spinelli O, Radich JP, Minden MD, Rowe JM, Luger S, Litzow MR, Tallman MS, Racevskis J, Zhang Y, Bhatia R, Kohlschmidt J, Mrózek K, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Evans WE, Jeha S, Pui CH, Yang J, Paietta E, Downing JR, Relling MV, Zhang J, Loh ML, Hunger SP, Mullighan CG. Nat Genet 51: 2019 296-307	281
Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen. Zhang H, Zhang Y, Zhou X, Wright S, Hyle J, Zhao L, An J, Zhao X, Shao Y, Xu B, Lee HM, Chen T, Zhou Y, Chen X, Lu R, Li C. Elife 9: 2020 e57858	23
Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL. Paietta E, Roberts KG, Wang V, Gu Z, Buck GAN, Pei D, Cheng C, Levine RL, Abdel-Wahab O, Cheng Z, Wu G, Qu C, Shi L, Pounds S, Willman CL, Harvey R, Racevskis J, Barinka J, Zhang Y, Dewald GW, Ketterling RP, Alejos D, Lazarus HM, Luger SM, Foroni L, Patel B, Fielding AK, Melnick A, Marks DI, Moorman AV, Wiernik PH, Rowe JM, Tallman MS, Goldstone AH, Mullighan CG, Litzow MR. Blood 138: 2021 948-958	46
Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia. Kimura S, Montefiori L, Iacobucci I, Zhao Y, Gao Q, Paietta EM, Haferlach C, Laird AD, Mead PE, Gu Z, Stock W, Litzow M, Rowe JM, Luger SM, Hunger SP, Ryland GL, Schmidt B, Ekert PG, Oshlack A, Grimmond SM, Rehn J, Breen J, Yeung D, White DL, Aldoss I, Jabbour EJ, Pui CH, Meggendorfer M, Walter W, Kern W, Haferlach T, Brady S, Zhang J, Roberts KG, Blombery P, Mullighan CG. Blood 139: 2022 3519-3531	18
Integrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines. Leo IR, Aswad L, Stahl M, Kunold E, Post F, Erkers T, Struyf N, Mermelekas G, Joshi RN, Gracia-Villacampa E, Östling P, Kallioniemi OP, Tamm KP, Siavelis I, Lehtiö J, Vesterlund M, Jafari R. Nat Commun 13: 2022 1691	19
Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion. Zhang M, Zhang H, Li Z, Bai L, Wang Q, Li J, Jiang M, Xue Q, Cheng N, Zhang W, Mao D, Chen Z, Huang J, Meng G, Chen Z, Chen SJ. Blood 140: 2022 1390-1407	5
The genomic landscape of pediatric acute lymphoblastic leukemia. Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, Cheng C, Dai Y, Devidas M, Qu C, Hill AN, Payne-Turner D, Ma X, Iacobucci I, Baviskar P, Wei L, Arunachalam S, Hagiwara K, Liu Y, Flasch DA, Liu Y, Parker M, Chen X, Elsayed AH, Pathak O, Li Y, Fan Y, Michael JR, Rusch M, Wilkinson MR, Foy S, Hedges DJ, Newman S, Zhou X, Wang J, Reilly C, Sioson E, Rice SV, Pastor Loyola V, Wu G, Rampersaud E, Reshmi SC, Gastier-Foster J, Guidry Auvil JM, Gesuwan P, Smith MA, Winick N, Carroll AJ, Heerema NA, Harvey RC, Willman CL, Larsen E, Raetz EA, Borowitz MJ, Wood BL, Carroll WL, Zweidler-McKay PA, Rabin KR, Mattano LA, Maloney KW, Winter SS, Burke MJ, Salzer W, Dunsmore KP, Angiolillo AL, Crews KR, Downing JR, Jeha S, Pui CH, Evans WE, Yang JJ, Relling MV, Gerhard DS, Loh ML, Hunger SP, Zhang J, Mullighan CG. Nat Genet 54: 2022 1376-1389	122
Identification of TCF3 germline variants in pediatric B-cell acute lymphoblastic leukemia. Escherich C, Chen W, Miyamoto S, Namikawa Y, Yang W, Teachey DT, Li Z, Raetz EA, Larsen E, Devidas M, Martin PL, Bowman WP, Wu G, Pui CH, Hunger SP, Loh ML, Takagi M, Yang JJ. Blood Adv 7: 2023 2177-2180	5
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response. Lee SHR, Yang W, Gocho Y, John A, Rowland L, Smart B, Williams H, Maxwell D, Hunt J, Yang W, Crews KR, Roberts KG, Jeha S, Cheng C, Karol SE, Relling MV, Rosner GL, Inaba H, Mullighan CG, Pui CH, Evans WE, Yang JJ. Nat Med 29: 2023 170-179	28
Targeting autophagy as a therapeutic strategy in pediatric acute lymphoblastic leukemia. Bwanika HC, Leo IR, Struyf N, Talanti A, Aswad L, Konnur A, Björklund AC, Heyman M, Rassidakis G, Erkers T, Seashore-Ludlow B, Jafari R, Pokrovskaja Tamm K. Sci Rep 14: 2024 4000	0