Open AccessDrug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL
Author(s) -
Bruch PeterMartin,
Giles Holly AR,
Kolb Carolin,
Herbst Sophie A,
Becirovic Tina,
Roider Tobias,
Lu Junyan,
Scheinost Sebastian,
Wagner Lena,
Huellein Jennifer,
Berest Ivan,
Kriegsmann Mark,
Kriegsmann Katharina,
Zgorzelski Christiane,
Dreger Peter,
Zaugg Judith B,
MüllerTidow Carsten,
Zenz Thorsten,
Huber Wolfgang,
Dietrich Sascha
Publication year - 2022
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.202110855
Subject(s) - biology , tumor microenvironment , drug resistance , epigenetics , cancer research , disease , immunology , immune system , genetics , gene , medicine
The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression.