PLX048247

GSE111014: Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [scRNA-seq]

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Chronic lymphocytic leukemia (CLL) is a genetically, epigenetically, and clinically heterogeneous disease. Despite this heterogeneity, the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib induces a sustained anti-CLL response in patients from all risk groups, in stark contrast to widespread drug resistance in other heterogeneous cancers. To understand the dynamics of ibrutinib response against the backdrop of patient-specific and heterogeneous disease manifestations, we followed individual courses of ibrutinib treatment in CLL patients at unprecedented resolution and detail. Combining phenotypic (flow cytometry), epigenetic (ATAC-seq), and transcriptional (single-cell RNA-seq) profiling of CLL cells and other immune cell populations with detailed clinical characterization, we inferred patient-specific molecular trajectories of treatment response. This analysis identified a highly consistent regulatory program shared across all patients, which starts with reduced NF-B binding followed by reduced expression of lineage defining transcription factors, erosion of CLL cell identity, and onset of a gene signature reminiscent of quiescence in several immune cell compartments. While this order of events was highly conserved across patients, and its gene signature was validated in an independent CLL cohort, we observed substantial patient-to-patient variability of the speed with which this program was executed. These results add time as a relevant facet to our understanding of CLL therapy and cancer heterogeneity, and they support the use of epigenome/transcriptome profiling to monitor patient-specific differences in drug response kinetics. SOURCE: Christoph Bock (cbock@cemm.oeaw.ac.at) - CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences