Proliferation of mature plasmacytoid dendritic cells in RUNX1-mutated Acute Myeloid Leukemia

Abstract

Abstract Introduction: Clonal expansion of mature plasmacytoid dendritic cells (pDCs), traditionally linked to chronic myelomonocytic leukemia, has recently been described in acute myeloid leukemia (AML), with an estimated prevalence of 5% and associated RUNX1 mutations in over 70% of cases (Xiao, W, Blood 2021). WHO-2022 classification includes myeloid neoplasms with pDC proliferation, defined by ≥2% pDCs mesured by flow cytometry in bone marrow or peripheral blood. Our study aimed to assess the frequency of RUNX1-mutated AML (RUNX1-AML) with pDC expansion and to explore clinical, biological, and prognostic characteristics. Methods: We retrospectively analyzed 38 adults diagnosed with RUNX1-AML from 2014 to 2025. Clinical and biological baseline data were collected, and flow cytometry records were reviewed to quantify pDCs (markers: CD141, CD123, CD4, CD11c, CD117, CD203c, CD34, CD56, HLA-DR, CD45). A 2% cutoff was applied per WHO 2022 criteria, with an additional subanalysis at 0.3% (lower pDC threshold in normal bone marrow). A targeted myeloid NGS panel of 39 genes was performed with a median depth of ×1400 with Illumina platform. Results: Of 38 RUNX1-AML patients, 5 (13%) had pDCs ≥2% (pDC-AML). This group showed differences in age (median 82.1 vs 62.2 years; p=0.0056), hemoglobin (10.5 vs 8.8 g/dL; p=0.04) and platelet counts (163.6 vs 65.2 ×10⁹/L; p=0.0023). Monocytic blast differentiation was more frequent by cytology (p=0.001) and flow cytometry (p=0.047). Blasts expressed higher levels of CD123, CD64, and CD4, though differences were not statistically significant. RUNX1 variant allele frequency was higher in pDC-AML (50.7% vs 34.5%), all of them showing truncating mutations (100% vs 48%, p=0.057). Concurrent TET2 mutations were more frequent in pDC-AML (60% vs 21%, p=0.033). Due to advanced age, none of pDC-AML patients received intensive therapy. Mortality was similar between groups. Subanalysis including patients with pDC >0.3% (n=9, 23%) yielded similar results. Conclusions: pDC expansion ≥2% was observed in 13% of RUNX1-AML patients, showing differences in age, hemoglobin and platelet counts, and also, more monocytic blast differentiation. This subgroup had more truncating RUNX1 mutations and frequent co-mutations in TET2. These findings suggest that pDC expansion identifies a distinct clinical and genetic subset within RUNX1-AML.