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Chronic lymphocytic leukemia

Minimal spatial heterogeneity in chronic lymphocytic leukemia at diagnosis

Leukemia volume 34, pages 1929–1933 (2020)Cite this article

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Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic B cells in peripheral blood (PB), lymph nodes (LN), bone marrow, and other tissues. CLL cells recirculate back-and-forth between the PB and LN where the crosstalk with nonneoplastic cells from the microenvironment favors their maintenance and proliferation [1]. Recently, whole-genome/exome sequencing (WGS/WES) studies focusing on large cohorts of samples from PB have described the mutational landscape of CLL, and uncovered a number of driver alterations associated with clinical outcome [2, 3]. Besides, these studies have highlighted a significant intra- and inter-patient heterogeneity that influence the evolution of the tumors [2,3,4,5]. Tumor heterogeneity related to diversification at different topographic sites has been observed in solid tumors and myeloid leukemias but it is less known in lymphoid neoplasms [6,7,8,9]. Based on the proposed continuous recirculation of CLL cells between the PB and LN, marked genetic differences between topographically distant CLL cells seems unlikely. Nonetheless, genomic data confirming (or questioning) this hypothesis is limited. Thus, we aimed to dissect the spatial genomic heterogeneity of CLL between PB and LN involvement in fifteen untreated, early-stage patients using WGS/WES and identified subtle differences in the global architecture of the tumor at PB and LN only in a fraction of patients. Spatial heterogeneity was not found among the well-established CLL-driver alterations.

Synchronous PB and LN DNA samples obtained close to diagnosis (within 1.5 years, n = 12) or at a stable phase of the disease (n = 3) from fifteen CLL patients were analyzed by WGS (n = 2) or WES (n = 13) (Table 1). Single nucleotide variants and short insertions and deletions (hereafter mutations), copy number alterations (CNA), and structural variants (SV) were extracted from WGS/WES (Supplementary Methods). The subclonal architecture of the tumors was reconstructed by integrating the allele frequency of the mutations, local copy number state and tumor purity to asses for differences in the topographic representation of clones (Supplementary Methods, Supplementary Table 1).

Table 1 Summary of the cohort studied.
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Fig. 1: WGS/WES comparison of synchronous PB and LN samples in CLL.

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Acknowledgements

This study was supported by the Instituto de Salud Carlos III and the European Regional Development Fund “Una manera de hacer Europa” (grant PMP15/00007), and the “la Caixa” Foundation (grant CLLEvolution-HR17-00221). EC is an Academia Researcher of the ‘Institució Catalana de Recerca i Estudis Avançats’ (ICREA) of the Generalitat de Catalunya. FN is supported by a pre-doctoral fellowship of the Ministerio de Economía y Competitividad (BES-2016-076372). FM is supported by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748).

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Authors and Affiliations

  1. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Ferran Nadeu, Marta Aymerich, Sílvia Beà, Armando López-Guillermo, Julio Delgado & Elías Campo

  2. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Ferran Nadeu, Marta Aymerich, Magda Pinyol, Sílvia Beà, Armando López-Guillermo, Julio Delgado & Elías Campo

  3. Barcelona Supercomputing Center (BSC), Barcelona, Spain

    Romina Royo & Ana Dueso-Barroso

  4. Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Francesco Maura

  5. Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK

    Francesco Maura & Kevin J. Dawson

  6. Hospital Clínic of Barcelona, Barcelona, Spain

    Marta Aymerich, Armando López-Guillermo, Julio Delgado & Elías Campo

  7. Unitat de Genòmica, IDIBAPS, Barcelona, Spain

    Magda Pinyol

  8. Universitat de Barcelona, Barcelona, Spain

    Armando López-Guillermo & Elías Campo

  9. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain

    Xose S. Puente

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  1. Ferran Nadeu
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  11. Xose S. Puente
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  12. Elías Campo
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Contributions

FN designed the study, collected data, analyzed data, and wrote the manuscript. RR collected and analyzed data. FM, KJD, AD, and XSP analyzed data. MA, MP, SB, ALG, and JD collected clinical data and samples. EC designed the study, collected samples and clinical data, analyzed data, wrote the manuscript, and supervised the research. All authors reviewed and approved the manuscript.

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Correspondence to Elías Campo.

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Nadeu, F., Royo, R., Maura, F. et al. Minimal spatial heterogeneity in chronic lymphocytic leukemia at diagnosis. Leukemia 34, 1929–1933 (2020). https://doi.org/10.1038/s41375-020-0730-3

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