Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

Studd, James B.; Cornish, Alex J.; Hoang, Phuc H.; Law, Philip; Houlston, Richard S.

doi:10.21203/rs.3.rs-366981/v1

Cited by 1 publication

(1 citation statement)

References 29 publications

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“…These findings are consistent with other bulk sequencing studies that also detected a limited number of mutations in cases from these subtypes. 4,27 Genomic data suggest that patients in these subgroups often harbor deletions of typical B-ALL genes, such as PAX5 , TCF3 , or ETV6 , but more rarely point mutations in signaling proteins or transcriptional regulators. 27 Single-cell sequencing of larger cohorts of B-ALL patients belonging to these subtypes is needed to validate our findings and might allow further fine tuning of these conclusions.…”

Section: Discussionmentioning

confidence: 99%

Monitoring of Leukemia Clones in B-cell Acute Lymphoblastic Leukemia at Diagnosis and During Treatment by Single-cell DNA Amplicon Sequencing

et al. 2022

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Acute lymphoblastic leukemia (ALL) is characterized by the presence of chromosomal changes, including numerical changes, translocations, and deletions, which are often associated with additional single-nucleotide mutations. In this study, we used single cell-targeted DNA sequencing to evaluate the clonal heterogeneity of B-ALL at diagnosis and during chemotherapy treatment. We designed a custom DNA amplicon library targeting mutational hotspot regions (in 110 genes) present in ALL, and we measured the presence of mutations and small insertions/deletions (indels) in bone marrow or blood samples from 12 B-ALL patients, with a median of 7973 cells per sample. Nine of the 12 cases showed at least 1 subclonal mutation, of which cases with PAX5 alterations or high hyperdiploidy (with intermediate to good prognosis) showed a high number of subclones (1 to 7) at diagnosis, defined by a variety of mutations in the JAK/STAT, RAS, or FLT3 signaling pathways. Cases with RAS pathway mutations had multiple mutations in FLT3, NRAS, KRAS, or BRAF in various clones. For those cases where we detected multiple mutational clones at diagnosis, we also studied blood samples during the first weeks of chemotherapy treatment. The leukemia clones disappeared during treatment with various kinetics, and few cells with mutations were easily detectable, even at low frequency (<0.1%). Our data illustrate that about half of the B-ALL cases show >2 subclones at diagnosis and that even very rare mutant cells can be detected at diagnosis or during treatment by single cell-targeted DNA sequencing.

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Section: Discussionmentioning

confidence: 99%