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PCGP Ph-like ALL

Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted

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
EGAD00001000976 Illumina HiSeq 2000 80
EGAD00001001016 Illumina HiSeq 2000 125
EGAD00001001054 Illumina HiSeq 2000 23
EGAD00001001432 Illumina HiSeq 2000 1337
EGAD00010000596 837
EGAD00010000598 1724
Publications Citations
Outcomes of children with BCR-ABL1–like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease.
J Clin Oncol 32: 2014 3012-3020
Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
N Engl J Med 371: 2014 1005-1015
Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia.
PLoS Genet 11: 2015 e1005262
Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.
Nat Commun 6: 2015 7553
Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia.
Cancer Cell 29: 2016 186-200
Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.
Nat Genet 48: 2016 1481-1489
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.
Nat Commun 7: 2016 13331
High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults.
J Clin Oncol 35: 2017 394-401
Leukaemic alterations of IKZF1 prime stemness and malignancy programs in human lymphocytes.
Cell Death Dis 9: 2018 526
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.
Proc Natl Acad Sci U S A 115: 2018 E11711-E11720
PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.
Nat Genet 51: 2019 296-307
Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia.
Nat Commun 10: 2019 2789
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
Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion.
Blood 140: 2022 1390-1407
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
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.
Nat Med 29: 2023 170-179
DUX4-r exerts a neomorphic activity that depends on GTF2I in acute lymphoblastic leukemia.
Sci Adv 9: 2023 eadi3771
Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data.
Sci Rep 14: 2024 6286