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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.

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 Illumina HiSeq 2000 16
EGAD00001004447 Illumina HiSeq 2000 128
EGAD00001004461 Illumina HiSeq 2000 1083
EGAD00001004463 Illumina HiSeq 2000 204
EGAD00010001635 415
EGAD00010001636 196
EGAD00010001637 539
EGAD00010001638 262
Publications Citations
PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.
Nat Genet 51: 2019 296-307
CICERO: a versatile method for detecting complex and diverse driver fusions using cancer RNA sequencing data.
Genome Biol 21: 2020 126
Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen.
Elife 9: 2020 e57858
Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.
Blood 138: 2021 948-958
Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy.
Blood Cancer Discov 2: 2021 326-337
Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia.
Blood 139: 2022 3519-3531
RNAseqCNV: analysis of large-scale copy number variations from RNA-seq data.
Leukemia 36: 2022 1492-1498
Multi-Cohort Transcriptomic Subtyping of B-Cell Acute Lymphoblastic Leukemia.
Int J Mol Sci 23: 2022 4574
Acute lymphoblastic leukemia displays a distinct highly methylated genome.
Nat Cancer 3: 2022 768-782
The genomic landscape of pediatric acute lymphoblastic leukemia.
Nat Genet 54: 2022 1376-1389
Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia.
Nat Commun 13: 2022 5401
RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL).
PLoS Genet 18: 2022 e1010300
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1.
NAR Cancer 4: 2022 zcac041
Identification of TCF3 germline variants in pediatric B-cell acute lymphoblastic leukemia.
Blood Adv 7: 2023 2177-2180
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.
Nat Med 29: 2023 170-179
Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms.
Commun Biol 6: 2023 295
Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia.
J Immunother Cancer 11: 2023 e006649