P059 | Splenomegaly in De Novo Acute Myeloid Leukemia Is Associated With Asxl1 Mutations and Peculiar Gene Expression and Clinical Profile.
Year: 2025
Type: article
Abstract: Splenomegaly is an event occurring in 10-40% of de novo acute myeloid leukemia (AML), recently linked to poorer prognosis. Studies in murine models have shown that loss of ASXL1 gene function leads to significant enlarged spleen volume, due to an increased infiltration of myeloid cells into the spleen. In light of this, we evaluated the occurrence of ASXL1 somatic mutations in the context of de novo AML patients presenting with splenomegaly at diagnosis, with the aim to unveil possible peculiar aspects of this rare clinical scenario. A total of 58 consecutive and de novo AML diagnosed at our institution from 2005 and 2022 with a splenic diameter larger than 12 cm (by ultrasound evaluation) were enrolled in this study. ASXL1 exons 12-13 were evaluated by direct sequencing. The mutational profile of 26 genes involved in myeloid malignancies was assessed by next-generation sequencing. To verify a possible link with a specific transcriptional profile, high-throughput RNA sequencing was conducted. ASXL1 mutations (ASXL1mut) were detected in 23/58 (40%) patients. All ASXL1 variants had a truncating effect. The most frequent variant was p.G646fs*12 [8/23 (35%) cases] followed by p.E635fs*15 [4/23 (17%) cases]. Deepening the molecular profile of cases for which sufficient material was available (45/58), ASXL1 resulted the most frequently mutated gene (23/45, 51%), followed by TET2 (18/45, 40%) and NRAS (16/45, 36%). No significant results emerged from mutual exclusivity analysis between variants detected. The ASXL1mut cases were significantly older than ASXL1wt (71 vs 64 years old, p=0.003), showed a significantly higher white blood cells count (31970/uL vs 17810/uL, p=0.044) and a higher platelet count (177700/uL vs 67700/uL, p=0.0006). On the contrary, the median bone marrow blasts percentage was lower in the ASXL1mut subset compared to ASXL1wt (36,4% vs 72,1%, p=0.002). Comparing the gene expression profile of ASXL1wt and ASXL1mut groups, a total of 1495 differentially expressed genes were detected, 811 protein coding genes (642 up-regulated and 169 down-regulated). Among them, the upregulation of PCDHB2 and of the couple LURAP1L/LURAP1L-AS1 (all involved in mechanisms of cellular interaction and migration) could play a role in the splenic infiltration of ASXL1mut leukemic cells. Overall, our data paves the way for further studies of an AML subgroup with a distinctive phenotype, whose prompt identification could improve patient management and therapeutic choice.
Authors: F. Tarantini, N. Coccaro, C. Cumbo, I. Redavid, L. Anelli, A. Zagaria, E. Parciante, M.R. Conserva, G. Tota, C. F. Minervini, A. Minervini, A. Mestice, V.P. Gagliardi, M. Delia, P. Carluccio, I. Attolico, A. Ricco, M.G. Macchia, M.F. Caratozzolo, F. Marzano, C. Telegrafo, S.N. Cox, B. Balech, A. Tullo, G. Specchia, P. Musto, F. Albano
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7094976777
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