The RTK-RAS signaling pathway is enriched in patients with rare acute myeloid leukemia harboring t(16;21)(p11;q22)/FUS::ERG.

ABSTRACT

Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/FUSERG is a rare AML subtype associated with poor prognosis. However, its clinical and molecular features remain poorly defined. We determined the clinicopathological, genomic, and transcriptomic characteristics and outcomes of patients with AML harboring FUSERG at our center. Thirty-six AML patients harboring FUSERG were identified, with an incidence rate of 0.3%. These patients were characterized by high lactate dehydrogenase levels (median 838.5 U/L), elevated bone marrow blast counts (median 71.5%), and a CD56-positive immunophenotype (94.3%). Notably, we found that RTK-RAS GTPase (RAS) pathway genes, including NRAS (33%) and PTPN11 (24%), were frequently mutated in this subtype. Transcriptome analysis revealed enrichment of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase (MAPK), and RAS signaling pathways and upregulation of BCL2, the target of venetoclax, in FUSERG AML compared to RUNX1RUNX1T1 AML, a more common AML subtype with good prognosis. The median event-free survival in patients with FUSERG AML was 11.9 (95% confidence interval [CI] 9.0-not available [NA]) months and the median overall survival was 18.2 (95% CI 12.4-NA) months. Allogeneic hematopoietic stem cell transplantation failed to improve outcomes. Overall, the high incidence of RTK-RAS pathway mutations and high expression of BCL2 may indicate promising therapeutic targets in this high-risk AML subset.