Splenomegaly in de novo acute myeloid leukemia is associated with ASXL1 mutations together with a distinct clinical and gene expression profile

Background: Splenomegaly is an event occurring in a variable range between 10–40% of de novo acute myeloid leukemia (AML), recently linked to poorer prognosis. Studies in murine models have shown that loss of the additional sex combs-like 1 (ASXL1) gene function leads to a significantly enlarged spleen volume, due to an increased infiltration of myeloid cells into the spleen. Methods: In 58 de novo AML patients presenting with splenomegaly at diagnosis, we evaluated the occurrence of ASXL1 somatic mutations, deepened the molecular profile and conducted high-throughput RNA sequencing, with the aim of unveiling possible peculiar aspects of this rare clinical scenario. Results: ASXL1 mutations (ASXL1mut) were detected in 23/58 (40%) patients, being the most frequently mutated gene, followed by TET2 and NRAS. ASXL1mut cases were significantly older than ASXL1wt (71 vs 64 years old, p = 0.003), showed a significantly higher white blood cells count (31,970/uL vs 17,810/uL, p = 0.044) and a higher platelet count (177,700/uL vs 67,700/uL, p = 0.0006). In contrast, 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 the ASXL1mut and ASXL1wt groups, we found the upregulation of PCDHB2 and LURAP1L/LURAP1L-AS1 (all involved in mechanisms of cellular interaction and migration) genes in the former group, unveiling a role in the splenic infiltration of ASXL1mut leukemic cells. Conclusions: 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 decision making.