LAUSR

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 (RUNX1) result in a familial platelet disorder with propensity to myeloid malignancies (RUNX1FPD), 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 RUNX1 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%) [5–8]. In CMML, RUNX1 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, RUNX1 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 RUNX1 with somatic RUNX1 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 RUNX1 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 assaysCGH) (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 * Mrinal M. Patnaik [email protected]