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Myelodysplastic syndrome

Clonal trajectories and cellular dynamics of myeloid neoplasms with SF3B1 mutations

Leukemia volume 35, pages 3324–3328 (2021)Cite this article

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Molecular lesions, either structural cytogenetic anomalies or gene mutations of known significance, occur in a step-wise fashion and are morphologic and prognostic markers in myeloid neoplasms (MNs). Current World Health Organization (WHO) classification categorizes patients with myelodysplastic syndrome (MDS) with ringed sideroblasts (RS) ≥15% or ≥5% RS with an SF3B1 mutation (SF3B1MT) as MDS-RS [1], a subtype in which the presence of SF3B1 mutations confers a favorable prognosis [2,3,4,5,6]. Although most patients with SF3B1MT have a classic phenotype, there is considerable heterogeneity within this subcategory including individual diversion of the originally favorable clinical phenotype. The disappearance of RS can be observed during the disease course of MNs, suggesting that new cellular shifts, due to the acquisition of additional lesions cooperating with/ or suppressing SF3B1MT might go along with evolution to acute myeloid leukemia (AML). Such courses are likely a result of the type and configuration of SF3B1MT, which potentially impact the disease course.

As compared to SF3B1SEC, SF3B1DOM were enriched in MDS (33 vs. 18%; P = 0.007), particularly with RS (27 vs. 9%; P = 0.006) while less present in sAML (12 vs. 23%; P = 0.03) (Table S3, Fig. S4). Eighty-percent of SF3B1DOM and 85% of SF3B1SEC occurred in the elderly (age ≥ 60 years). No differences in sex distribution and hematological parameters were reported except for bi-cytopenia (52 vs. 36%; P = 0.01), more dysplastic myeloid cells (53 vs. 29%; P = 0.01) and bi-lineage dysplasia (47 vs. 26%; P = 0.02, Table S3) in patients with SF3B1SEC vs. SF3B1DOM. In contrast, the bone marrow of SF3B1DOM patients was more often normocellular (46 vs. 29%; P = 0.02) and enriched with RS (Table S3); the latter also correlated with higher SF3B1MT VAFs (Fig. 1C, Fig. S5). Interestingly, although patients with SF3B1SEC had shorter OS than those with SF3B1DOM (21.9 vs. 41.1 mo.; P < 0.03; Fig. 1B), when dichotomized according to different SF3B1MT VAF ranges (>40%, 20–40%, <20%), no significant OS differences were observed (Fig. S6A) even when the SF3B1MT clonal ranks were considered (Fig. S6B–D).

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Fig. 1: Characteristics, mutational associations and prognostic implications of clonal events in SF3B1 mutant myeloid neoplasms.
Fig. 2: The clonal trajectories of SF3B1 mutations.

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Acknowledgements

We thank the following sources of funding: Aplastic Anemia and MDS International Foundation Research Grant (VV and JPM), Vera and Joseph Dresner Foundation-MDS Research Fund (VV), VeloSano Pilot Award (VV), NIH/NHLBI R35HL135795 (JPM), R01HL132071 (JPM), The Henry and Marilyn Taub Foundation (JPM). We thank the team of Mission Bio for technical expertise on single cell-DNA sequencing and The Cancer Genome Atlas (TCGA), The BEAT AML Master Trial and The German-Austrian Study Group for data accessibility.

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Hassan Awada, Cassandra M. Kerr, Arda Durmaz, Vera Adema, Carmelo Gurnari, Simona Pagliuca, Misam Zawit, Sunisa Kongkiatkamon, Yogen Saunthararajah, Jaroslaw P. Maciejewski & Valeria Visconte

  2. Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA

    Heesun J. Rogers

  3. Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Yogen Saunthararajah, Mikkael A. Sekeres, Hetty Carraway & Jaroslaw P. Maciejewski

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  1. Hassan Awada
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Contributions

Contribution: HA collected, analyzed and interpreted the data, designed the tables and figures, and wrote the manuscript; CMK, AD developed DNA-sequencing methodologies, analyzed single cell-DNA sequencing, and edited the manuscript; VA; CG, SP, MZ, SK, collected the data and edited the manuscript; HJR collected clinical info and provided critical review to the manuscript; YS, MAS, HEC provided patients and important insights to the manuscript preparation; JPM provided patients, laboratory space and facilities, granted a collection of clinical charts and molecular annotated databases, sponsored the DNA sequencing studies, and edited the manuscript; VV conceived the idea, designed the study, supervised the work, interpreted and analyzed the data and content, and wrote the manuscript.

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Correspondence to Valeria Visconte.

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Awada, H., Kerr, C.M., Durmaz, A. et al. Clonal trajectories and cellular dynamics of myeloid neoplasms with SF3B1 mutations. Leukemia 35, 3324–3328 (2021). https://doi.org/10.1038/s41375-021-01176-7

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