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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Veröffentlicht in:	Nature genetics Jg. 55; H. 7; S. 1186 - 1197
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.07.2023 Nature Publishing Group
Schlagworte:	38/91 45 45/23 631/208/199 631/67/1990/283/2125 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
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-023-01429-4