Mullighan - PAX5-driven Subtypes

Using integrated genomic analysis of 1.988 childhood and adult cases, we describe a revised taxonomy of B-cell acute lymphoblastic leukemia, which incorporates 23 subtypes defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations. Two subtypes have frequent alterations of the B lymphoid transcription factor gene PAX5. One, PAX5alt, has diverse PAX5 alterations, and a second subtype is defined by a single mutation, PAX5 P80R. We show that P80R impairs B lymphoid development and promotes the development of B-ALL in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.

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

8 Datasets 19 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
EGAD00001004446	WGS files for Mullighan PAX5_B-ALL paper titled "PAX5-driven Subtypes of B-cell Acute Lymphoblastic Leukemia"	Illumina HiSeq 2000	16
EGAD00001004447	WES files for Mullighan PAX5_B-ALL paper titled "PAX5-driven Subtypes of B-cell Acute Lymphoblastic Leukemia"	Illumina HiSeq 2000	128
EGAD00001004461	RNAseq files (dataset 1 of 2) for Mullighan PAX5_B-ALL paper titled "PAX5-driven Subtypes of B-cell Acute Lymphoblastic Leukemia"	Illumina HiSeq 2000	1083
EGAD00001004463	RNAseq files (dataset 2 of 2) for Mullighan PAX5_B-ALL paper titled "PAX5-driven Subtypes of B-cell Acute Lymphoblastic Leukemia"	Illumina HiSeq 2000	204
EGAD00010001635	Over 1.87 million SNP and CNV loci are screened by Affymetrix SNP 6.0 array		415
EGAD00010001636	Over 2.5 million SNP and CNV loci are screened by Illumina Infinium Omni2.5Exome-8 Kit		196
EGAD00010001637	Over 1.87 million SNP and CNV loci are screened by Affymetrix SNP 6.0 array		539
EGAD00010001638	Over 2.5 million SNP and CNV loci are screened by Illumina Infinium Omni2.5Exome-8 Kit		262

Publications	Citations
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
CICERO: a versatile method for detecting complex and diverse driver fusions using cancer RNA sequencing data. Tian L, Li Y, Edmonson MN, Zhou X, Newman S, McLeod C, Thrasher A, Liu Y, Tang B, Rusch MC, Easton J, Ma J, Davis E, Trull A, Michael JR, Szlachta K, Mullighan C, Baker SJ, Downing JR, Ellison DW, Zhang J. Genome Biol 21: 2020 126	57
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	22
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
Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy. Jeha S, Choi J, Roberts KG, Pei D, Coustan-Smith E, Inaba H, Rubnitz JE, Ribeiro RC, Gruber TA, Raimondi SC, Karol SE, Qu C, Brady SW, Gu Z, Yang JJ, Cheng C, Downing JR, Evans WE, Relling MV, Campana D, Mullighan CG, Pui CH. Blood Cancer Discov 2: 2021 326-337	60
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
RNAseqCNV: analysis of large-scale copy number variations from RNA-seq data. Bařinka J, Hu Z, Wang L, Wheeler DA, Rahbarinia D, McLeod C, Gu Z, Mullighan CG. Leukemia 36: 2022 1492-1498	18
Multi-Cohort Transcriptomic Subtyping of B-Cell Acute Lymphoblastic Leukemia. Mäkinen VP, Rehn J, Breen J, Yeung D, White DL. Int J Mol Sci 23: 2022 4574	9
Acute lymphoblastic leukemia displays a distinct highly methylated genome. Hetzel S, Mattei AL, Kretzmer H, Qu C, Chen X, Fan Y, Wu G, Roberts KG, Luger S, Litzow M, Rowe J, Paietta E, Stock W, Mardis ER, Wilson RK, Downing JR, Mullighan CG, Meissner A. Nat Cancer 3: 2022 768-782	16
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
Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia. Zhao X, Wang P, Diedrich JD, Smart B, Reyes N, Yoshimura S, Zhang J, Yang W, Barnett K, Xu B, Li Z, Huang X, Yu J, Crews K, Yeoh AEJ, Konopleva M, Wei CL, Pui CH, Savic D, Yang JJ. Nat Commun 13: 2022 5401	5
RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL). Rehn J, Mayoh C, Heatley SL, McClure BJ, Eadie LN, Schutz C, Yeung DT, Cowley MJ, Breen J, White DL. PLoS Genet 18: 2022 e1010300	12
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1. Closa A, Reixachs-Solé M, Fuentes-Fayos AC, Hayer KE, Melero JL, Adriaanse FRS, Bos RS, Torres-Diz M, Hunger SP, Roberts KG, Mullighan CG, Stam RW, Thomas-Tikhonenko A, Castaño JP, Luque RM, Eyras E. NAR Cancer 4: 2022 zcac041	4
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
Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms. Taghi Khani A, Kumar A, Sanchez Ortiz A, Radecki KC, Aramburo S, Lee SJ, Hu Z, Damirchi B, Lorenson MY, Wu X, Gu Z, Stohl W, Sanz I, Meffre E, Müschen M, Forman SJ, Koff JL, Walker AM, Swaminathan S. Commun Biol 6: 2023 295	1
Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia. Kumar A, Taghi Khani A, Duault C, Aramburo S, Sanchez Ortiz A, Lee SJ, Chan A, Chan A, McDonald T, Huang M, Lacayo NJ, Sakamoto KM, Yu J, Hurtz C, Carroll M, Tasian SK, Ghoda L, Marcucci G, Gu Z, Rosen ST, Armenian S, Izraeli S, Chen CW, Caligiuri MA, Forman SJ, Maecker HT, Swaminathan S. J Immunother Cancer 11: 2023 e006649	7
Reproducible Bioinformatics Analysis Workflows for Detecting <i>IGH</i> Gene Fusions in B-Cell Acute Lymphoblastic Leukaemia Patients. Thomson AJ, Rehn JA, Heatley SL, Eadie LN, Page EC, Schutz C, McClure BJ, Sutton R, Dalla-Pozza L, Moore AS, Greenwood M, Kotecha RS, Fong CY, Yong ASM, Yeung DT, Breen J, White DL. Cancers (Basel) 15: 2023 4731	1
Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression. Molina O, Ortega-Sabater C, Thampi N, Fernández-Fuentes N, Guerrero-Murillo M, Martínez-Moreno A, Vinyoles M, Velasco-Hernández T, Bueno C, Trincado JL, Granada I, Campos D, Giménez C, Boer JM, den Boer ML, Calvo GF, Camós M, Fuster JL, Velasco P, Ballerini P, Locatelli F, Mullighan CG, Spierings DCJ, Foijer F, Pérez-García VM, Menéndez P. EMBO Mol Med 16: 2024 64-92	1