Unveiling the dynamics and molecular landscape of a rare chronic lymphocytic leukemia subpopulation driving refractoriness: insights from single-cell RNA sequencing

. 2024 Oct ; 18 (10) : 2541-2553. [epub] 20240521

Jazyk angličtina Země Spojené státy americké Médium print-electronic

Typ dokumentu časopisecké články, kazuistiky

Perzistentní odkaz   https://www.medvik.cz/link/pmid38770541

Grantová podpora
European Union - Next Generation EU
FNBr 65269705 Ministerstvo Zdravotnictví Ceské Republiky
NU-20-08-00314 Ministerstvo Zdravotnictví Ceské Republiky
23-05561S Grantová Agentura České Republiky
MUNI/A/1558/2023 Lékařská fakulta, Masarykova univerzita

Early identification of resistant cancer cells is currently a major challenge, as their expansion leads to refractoriness. To capture the dynamics of these cells, we made a comprehensive analysis of disease progression and treatment response in a chronic lymphocytic leukemia (CLL) patient using a combination of single-cell and bulk genomic methods. At diagnosis, the patient presented with unfavorable genetic markers, including notch receptor 1 (NOTCH1) mutation and loss(11q). The initial and subsequent treatment lines did not lead to a durable response and the patient developed refractory disease. Refractory CLL cells featured substantial dysregulation in B-cell phenotypic markers such as human leukocyte antigen (HLA) genes, immunoglobulin (IG) genes, CD19 molecule (CD19), membrane spanning 4-domains A1 (MS4A1; previously known as CD20), CD79a molecule (CD79A) and paired box 5 (PAX5), indicating B-cell de-differentiation and disease transformation. We described the clonal evolution and characterized in detail two cell populations that emerged during the refractory disease phase, differing in the presence of high genomic complexity. In addition, we successfully tracked the cells with high genomic complexity back to the time before treatment, where they formed a rare subpopulation. We have confirmed that single-cell RNA sequencing enables the characterization of refractory cells and the monitoring of their development over time.

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Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910–1916. PubMed

Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848–1854. PubMed

Parikh SA, Strati P, Tsang M, West CP, Shanafelt TD. Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta‐analysis. Blood. 2016;127(14):1752–1760. PubMed

Mansouri L, Thorvaldsdottir B, Sutton L‐A, Karakatsoulis G, Meggendorfer M, Parker H, et al. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY. Leukemia. 2023;37(2):339–347. PubMed PMC

Puente XS, Beà S, Valdés‐Mas R, Villamor N, Gutiérrez‐Abril J, Martín‐Subero JI, et al. Non‐coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526(7574):519–524. PubMed

Landau DA, Tausch E, Taylor‐Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526(7574):525–530. PubMed PMC

Nadeu F, Delgado J, Royo C, Baumann T, Stankovic T, Pinyol M, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127(17):2122–2130. PubMed PMC

Hallek M, Cheson BD, Catovsky D, Caligaris‐Cappio F, Dighiero G, Döhner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745–2760. PubMed

Eichhorst B, Robak T, Montserrat E, Ghia P, Niemann CU, Kater AP, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow‐up. Ann Oncol. 2021;32(1):23–33. PubMed

Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole‐genome sequencing. Nature. 2012;481(7382):506–510. PubMed PMC

Malcikova J, Pavlova S, Kunt Vonkova B, Radova L, Plevova K, Kotaskova J, et al. Low‐burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options. Blood. 2021;138(25):2670–2685. PubMed PMC

Hallek M, Cheson BD, Catovsky D, Caligaris‐Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute‐working group 1996 guidelines. Blood. 2008;111(12):5446–5456. PubMed PMC

Hao Y, Hao S, Andersen‐Nissen E, Mauck WM, Zheng S, Butler A, et al. Integrated analysis of multimodal single‐cell data. Cell. 2021;184(13):3573–3587.e29. PubMed PMC

Finak G, McDavid A, Yajima M, Deng J, Gersuk V, Shalek AK, et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single‐cell RNA sequencing data. Genome Biol. 2015;16:278. PubMed PMC

Navrkalova V, Plevova K, Hynst J, Pal K, Mareckova A, Reigl T, et al. LYmphoid NeXt‐generation sequencing (LYNX) panel: a comprehensive capture‐based sequencing tool for the analysis of prognostic and predictive markers in lymphoid malignancies. J Mol Diagn. 2021;23(8):959–974. PubMed

Miller CA, McMichael J, Dang HX, Maher CA, Ding L, Ley TJ, et al. Visualizing tumor evolution with the fishplot package for R. BMC Genomics. 2016;17(1):880. PubMed PMC

Malcikova J, Stano‐Kozubik K, Tichy B, Kantorova B, Pavlova S, Tom N, et al. Detailed analysis of therapy‐driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. Leukemia. 2015;29(4):877–885. PubMed PMC

Kubesova B, Pavlova S, Malcikova J, Kabathova J, Radova L, Tom N, et al. Low‐burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status. Leukemia. 2018;32(2):450–461. PubMed PMC

Pavlova S, Smardova J, Tom N, Trbusek M. Detection and functional analysis of TP53 mutations in CLL. Methods Mol Biol. 2019;1881:63–81. PubMed

Ishioka C, Frebourg T, Yan YX, Vidal M, Friend SH, Schmidt S, et al. Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nat Genet. 1993;5(2):124–129. PubMed

Cobaleda C, Jochum W, Busslinger M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature. 2007;449(7161):473–477. PubMed

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