Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia

In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1 , is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia,...

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Published in:Nature genetics Vol. 55; no. 7; pp. 1186 - 1197
Main Authors: Kim, Jaeseung C., Chan-Seng-Yue, Michelle, Ge, Sabrina, Zeng, Andy G. X., Ng, Karen, Gan, Olga I., Garcia-Prat, Laura, Flores-Figueroa, Eugenia, Woo, Tristan, Zhang, Amy Xin Wei, Arruda, Andrea, Chithambaram, Shivapriya, Dobson, Stephanie M., Khoo, Amanda, Khan, Shahbaz, Ibrahimova, Narmin, George, Ann, Tierens, Anne, Hitzler, Johann, Kislinger, Thomas, Dick, John E., McPherson, John D., Minden, Mark D., Notta, Faiyaz
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.07.2023
Nature Publishing Group
Subjects:
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Agriculture
Animal Genetics and Genomics
Antigens
BCR-ABL protein
Biomedical and Life Sciences
Biomedicine
Blood
Cancer Research
Cell cycle
Cell differentiation
Cell Differentiation - genetics
Clinical outcomes
Cloning
Depth profiling
Disease
Flow cytometry
Fusion Proteins, bcr-abl - genetics
Fusion Proteins, bcr-abl - metabolism
Gene expression
Gene Expression Profiling
Gene Function
Genomics
Genotype & phenotype
Heterogeneity
Human Genetics
Humans
Kinases
Kruskal-Wallis test
Leukemia
Lymphatic leukemia
Lymphocytes B
Maturation
Mutation
Patients
Phenotypes
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Progenitor cells
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Protein-tyrosine kinase
Stem cells
Thermal resistance
Transcriptome - genetics
Transcriptomics
Tyrosine
ISSN:1061-4036, 1546-1718, 1546-1718
Online Access:Get full text
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Summary:In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1 , is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes. A later arrest was associated with lineage fidelity, durable leukemia remissions and improved patient outcomes. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. Interestingly, these events were absent in BCR-ABL1 + preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms. Transcriptomic analysis of BCR-ABL1 lymphoblastic leukemia identifies three subgroups, each associated with a maturation arrest at a specific stage of B-cell progenitor differentiation and distinct genetic and clinical features.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-023-01429-4