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FIGURE 2 from Single-cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy

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posted on 2024-02-12, 14:20 authored by Ignacio Campillo-Marcos, Marta Casado-Pelaez, Veronica Davalos, Gerardo Ferrer, Caterina Mata, Elisabetta Mereu, Gael Roué, David Valcárcel, Antonieta Molero, Lurdes Zamora, Blanca Xicoy, Laura Palomo, Pamela Acha, Ana Manzanares, Magnus Tobiasson, Eva Hellström-Lindberg, Francesc Solé, Manel Esteller

Distribution of mutant clones and CNVs at diagnosis in patients with the studied MDS. A, Proportion of mutant clones over all mutant cells at diagnosis in each patient, colored by clone abundance. Upper bar plot illustrates number of clones at diagnosis and the middle bar indicates the response status (green, responders; magenta, nonresponders). Note that patient #10 is not included because no mutant clones were found using our gene panel. B, Number of mutant clones at diagnosis (left); Shannon diversity index computed among mutant clones at diagnosis (middle); predominant mutant clone size with respect to other mutant clones at diagnosis (right). R, responders; NR, nonresponders. C, Percentage of patients with mutations in each gene in the predominant clone at diagnosis (left); Percentage of patients with mutations in each gene in the first clone at diagnosis (right). D, Proportion of responders and nonresponder patients with CHIP mutations (TET2, DNMT3A, and ASXL1) in first (left) and predominant (right) clones at diagnosis. E, Oncoprint of CNVs in the patient cohort at diagnosis. F, Median per amplicon ploidy of the mutant clones for patients with CNVs (patients #2, #3, #5, #8, #9, and #13).

Funding

Government of Catalonia | Departament d'Empresa i Coneixement, Generalitat de Catalunya (Ministry of Business and Knowledge, Government of Catalonia)

Ministerio de Ciencia e Innovación (MCIN)

Fundación Cellex (Cellex Foundation)

Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona (“la Caixa” Foundation)

Fundación Científica Asociación Española Contra el Cáncer (AECC)

EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)

History

ARTICLE ABSTRACT

Alterations in epigenetic marks, such as DNA methylation, represent a hallmark of cancer that has been successfully exploited for therapy in myeloid malignancies. Hypomethylating agents (HMA), such as azacitidine, have become standard-of-care therapy to treat myelodysplastic syndromes (MDS), myeloid neoplasms that can evolve into acute myeloid leukemia. However, our capacity to identify who will respond to HMAs, and the duration of response, remains limited. To shed light on this question, we have leveraged the unprecedented analytic power of single-cell technologies to simultaneously map the genome and immunoproteome of MDS samples throughout clinical evolution. We were able to chart the architecture and evolution of molecular clones in precious paired bone marrow MDS samples at diagnosis and posttreatment to show that a combined imbalance of specific cell lineages with diverse mutational profiles is associated with the clinical response of patients with MDS to hypomethylating therapy. MDS are myeloid clonal hemopathies with a low 5-year survival rate, and approximately half of the cases do not respond to standard HMA therapy. Our innovative single-cell multiomics approach offers valuable biological insights and potential biomarkers associated with the demethylating agent efficacy. It also identifies vulnerabilities that can be targeted using personalized combinations of small drugs and antibodies.