Drug-microenvironment Perturbations Reveal Resistance Mechanisms and Prognostic Subgroups in CLL

Overview

Journal Mol Syst Biol

Specialty Molecular Biology

Date 2022 Aug 12

PMID 35959629

Authors

Peter-Martin Bruch

Holly Ar Giles

Carolin Kolb

Sophie A Herbst

Tina Becirovic

Tobias Roider

Junyan Lu

Sebastian Scheinost

Lena Wagner

Jennifer Huellein

Ivan Berest

Mark Kriegsmann

Katharina Kriegsmann

Christiane Zgorzelski

Peter Dreger

Judith B Zaugg

Carsten Muller-Tidow

Thorsten Zenz

Wolfgang Huber

Sascha Dietrich

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs).

Schmitt L, Hoppe J, Cea-Medina P, Bruch P, Krings K, Lechtenberg I Cell Death Discov. 2024; 10(1):279.

PMID: 38862521 PMC: 11167047. DOI: 10.1038/s41420-024-02056-6.

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death.

Mantione M, Meloni M, Sana I, Bordini J, Del Nero M, Riba M Cell Death Dis. 2024; 15(3):224.

PMID: 38494482 PMC: 10944843. DOI: 10.1038/s41419-024-06602-z.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.

Liebers N, Bruch P, Terzer T, Hernandez-Hernandez M, Paramasivam N, Fitzgerald D Nat Cancer. 2023; 4(12):1648-1659.

PMID: 37783805 PMC: 10733146. DOI: 10.1038/s43018-023-00645-5.

Comparing the value of mono- vs coculture for high-throughput compound screening in hematological malignancies.

Herbst S, Kim V, Roider T, Schitter E, Bruch P, Liebers N Blood Adv. 2023; 7(19):5925-5936.

PMID: 37352275 PMC: 10558604. DOI: 10.1182/bloodadvances.2022009652.

Recent revelations and future directions using single-cell technologies in chronic lymphocytic leukemia.

Oder B, Chatzidimitriou A, Langerak A, Rosenquist R, Osterholm C Front Oncol. 2023; 13:1143811.

PMID: 37091144 PMC: 10117666. DOI: 10.3389/fonc.2023.1143811.

References

Sarkans U, Gostev M, Athar A, Behrangi E, Melnichuk O, Ali A . The BioStudies database-one stop shop for all data supporting a life sciences study. Nucleic Acids Res. 2017; 46(D1):D1266-D1270. PMC: 5753238. DOI: 10.1093/nar/gkx965. View

Roider T, Seufert J, Uvarovskii A, Frauhammer F, Bordas M, Abedpour N . Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels. Nat Cell Biol. 2020; 22(7):896-906. DOI: 10.1038/s41556-020-0532-x. View

Buenrostro J, Wu B, Chang H, Greenleaf W . ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide. Curr Protoc Mol Biol. 2015; 109:21.29.1-21.29.9. PMC: 4374986. DOI: 10.1002/0471142727.mb2129s109. View

Bruch P, Giles H, Kolb C, Herbst S, Becirovic T, Roider T . Drug-microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL. Mol Syst Biol. 2022; 18(8):e10855. PMC: 9372727. DOI: 10.15252/msb.202110855. View

Yu G, Wang L, He Q . ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics. 2015; 31(14):2382-3. DOI: 10.1093/bioinformatics/btv145. View

Dahl R, Rao S, Barton K, Simon M . PU.1 exhibits partial functional redundancy with Spi-B, but not with Ets-1 or Elf-1. Blood. 2001; 97(9):2908-12. DOI: 10.1182/blood.v97.9.2908. View

Akalin A, Franke V, Vlahovicek K, Mason C, Schubeler D . Genomation: a toolkit to summarize, annotate and visualize genomic intervals. Bioinformatics. 2014; 31(7):1127-9. DOI: 10.1093/bioinformatics/btu775. View

Baumann T, Moia R, Gaidano G, Delgado J, Condoluci A, Villamor N . Lymphocyte doubling time in chronic lymphocytic leukemia modern era: a real-life study in 848 unselected patients. Leukemia. 2021; 35(8):2325-2331. DOI: 10.1038/s41375-021-01149-w. View

Ten Hacken E, Burger J . Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment. Biochim Biophys Acta. 2015; 1863(3):401-413. PMC: 4715999. DOI: 10.1016/j.bbamcr.2015.07.009. View

10.

Beekman R, Chapaprieta V, Russinol N, Vilarrasa-Blasi R, Verdaguer-Dot N, Martens J . The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia. Nat Med. 2018; 24(6):868-880. PMC: 6363101. DOI: 10.1038/s41591-018-0028-4. View

11.

Oppermann S, Ylanko J, Shi Y, Hariharan S, Oakes C, Brauer P . High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells. Blood. 2016; 128(7):934-47. PMC: 5000578. DOI: 10.1182/blood-2015-12-687814. View

12.

Ahn I, Farooqui M, Tian X, Valdez J, Sun C, Soto S . Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018; 131(21):2357-2366. PMC: 5969380. DOI: 10.1182/blood-2017-12-820910. View

13.

Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B . The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2010; 117(2):563-74. PMC: 3031480. DOI: 10.1182/blood-2010-05-284984. View

14.

Friedman J, Hastie T, Tibshirani R . Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010; 33(1):1-22. PMC: 2929880. View

15.

Herbst S, Vesterlund M, Helmboldt A, Jafari R, Siavelis I, Stahl M . Proteogenomics refines the molecular classification of chronic lymphocytic leukemia. Nat Commun. 2022; 13(1):6226. PMC: 9584885. DOI: 10.1038/s41467-022-33385-8. View

16.

Edgar R, Domrachev M, Lash A . Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2001; 30(1):207-10. PMC: 99122. DOI: 10.1093/nar/30.1.207. View

17.

Rendeiro A, Schmidl C, Strefford J, Walewska R, Davis Z, Farlik M . Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks. Nat Commun. 2016; 7:11938. PMC: 5494194. DOI: 10.1038/ncomms11938. View

18.

Dietrich S, Oles M, Lu J, Sellner L, Anders S, Velten B . Drug-perturbation-based stratification of blood cancer. J Clin Invest. 2017; 128(1):427-445. PMC: 5749541. DOI: 10.1172/JCI93801. View

19.

Burger J, Tedeschi A, Barr P, Robak T, Owen C, Ghia P . Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015; 373(25):2425-37. PMC: 4722809. DOI: 10.1056/NEJMoa1509388. View

20.

Wilkerson M, Hayes D . ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010; 26(12):1572-3. PMC: 2881355. DOI: 10.1093/bioinformatics/btq170. View