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Myelodysplastic syndrome

Spectrum of abnormalities and clonal transformation in germline RUNX1 familial platelet disorder and a genomic comparative analysis with somatic RUNX1 mutations in MDS/MPN overlap neoplasms

Leukemia volume 34, pages 2519–2524 (2020)Cite this article

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The Runt-related transcription factor 1 (RUNX1) gene encodes a transcription factor that plays a crucial role in embryogenesis and definitive hematopoiesis [1]. Germline RUNX1 mutations (RUNX1MT) result in a familial platelet disorder with propensity to myeloid malignancies (RUNX1-FPD), a rare autosomal dominant condition characterized by mild to moderate thrombocytopenia, qualitative platelet defects, and inherent predisposition to develop hematological malignancies such as myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and T-cell acute lymphoblastic leukemia (T-ALL) [2]. The lifetime risk of developing a myeloid malignancy in RUNX1-FPD is about 30–40%, with a median age at onset of 33 years [3]. In addition, germline pathogenic RUNX1 variants can be found in up to 29% of the families with two or more cases of AML or MDS [4]. Somatic RUNX1MT have been identified as recurrent abnormalities in myeloid neoplasms, including AML (10%), MDS (12%), myeloproliferative neoplasms (MPN, 2–4%), and MDS/MPN overlap syndromes such as chronic myelomonocytic leukemia (CMML, 15%) [5,6,7,8]. In CMML, RUNX1MT are associated with a higher risk of leukemic transformation (LT), especially in the context of mutations located in the C-terminal region, with a recent study also demonstrating an adverse impact on overall survival (OS) [7, 9]. In addition, RUNX1MT have been identified in ~2–4% of patient with clonal cytopenias of unclear significance (CCUS), a premalignant condition associated with a probability of developing a myeloid neoplasm 14 times higher than that of patients with no evidence of clonal disease [10, 11]. We carried out this study to (i) define the genomic landscape of clonal evolution in RUNX1-FPD patients, (ii) compare and contrast germline RUNX1MT with somatic RUNX1MT seen in patients with MDS/MPN overlap syndromes (due to the availability of a well-defined data set) and (iii) assess phenotypic and survival differences between somatic RUNX1MT and RUNX1 wild-type patients with MDS/MPN overlap syndromes.

With due approval from the Mayo Clinic (Rochester, MN, USA) institutional review board, after obtaining written informed consent, families with RUNX1-FPD detected by germline sequencing of buccal swab-derived DNA or skin fibroblast-derived DNA (target capture-NGS and/or whole exome sequencing) and deletion/duplication assays (array comparative genomic hybridization assays-CGH) (Supplementary Table 1) and patients with 2016, World Health Organization (WHO)-defined MDS/MPN overlap syndromes (except juvenile myelomonocytic leukemia) were included in the study. Index patients with RUNX1-FPD underwent bone marrow (BM) biopsies and in select cases target capture-NGS at diagnosis and then as indicated for follow-up, or at disease progression (to assess for clonal evolution). For the purposes of this study, CCUS was defined by the presence of ≥1 acquired (somatic) mutations in leukemia-associated genes (variant allele frequency/VAF ≥ 2%), detected in the context of worsening thrombocytopenia (from baseline), or newly detected anemia/leukopenia, with BM findings being nondiagnostic for an underlying myeloid neoplasm (MDS/AML). All MDS/MPN overlap syndrome patients underwent a 29-gene panel target capture-NGS assay on BM samples obtained at diagnosis, or at first referral, by previously described methods [12].

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Fig. 1: Clinical and mutational characteristics of patients with germline and somatic RUNX1 mutations.

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Acknowledgements

The authors would like to acknowledge the “Henry J Predolin Foundation” for Leukemia research for helping fund this research. We would also like to acknowledge all participating patients and their family members who have consented for this study.

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Authors and Affiliations

  1. Mayo Clinic Alix School of Medicine, Rochester, MN, USA

    Emma C. DiFilippo

  2. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Giacomo Coltro, Ryan M. Carr, Abhishek A. Mangaonkar, Moritz Binder, Naseema Gangat, Alexandra Wolanskyj, Rajiv K. Pruthi, Terra Lasho, Christy Finke, Ayalew Tefferi & Animesh Pardanani

  3. Division of Pediatric Hematology, Mayo Clinic, Rochester, MN, USA

    Shakila P. Khan, Vilmarie Rodriguez & Mrinal M. Patnaik

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Dong Chen, Rong He & David S. Viswanatha

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Correspondence to Mrinal M. Patnaik.

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DiFilippo, E.C., Coltro, G., Carr, R.M. et al. Spectrum of abnormalities and clonal transformation in germline RUNX1 familial platelet disorder and a genomic comparative analysis with somatic RUNX1 mutations in MDS/MPN overlap neoplasms. Leukemia 34, 2519–2524 (2020). https://doi.org/10.1038/s41375-020-0752-x

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