Genetic and clinical distinction between aggressive NK-cell leukemia and extranodal NK/T-cell lymphoma with bone marrow involvement.

Aggressive NK-cell leukemia (ANKL) shares common clinicopathological features with extranodal NK/T-cell lymphoma with bone marrow (BM) involvement (ENKTL-BM), making their distinction challenging in BM examination. Despite numerous studies, genetic differences between the two diseases remained largely unclear. To investigate the genetic and clinical differences between ANKL and ENKTL-BM, we performed targeted sequencing of 282 genes and survival analyses on 15 ANKL and 5 ENKTL-BM patients. Mutation frequency of FAT family genes was higher in ANKL than in ENKTL-BM (80.0% vs. 0.0%, P = 0.004), and FAT1 gene mutations were associated with significantly lower survival rates in ANKL patients (P = 0.002). Copy number alterations including 11q loss and 4q loss were detected exclusively in ANKL. The interval from symptom onset to death was significantly shorter (113.0 vs. 440.5 days, P = 0.027) and survival rate was significantly lower (P = 0.004) in ANKL than in ENKTL-BM. In conclusion, ANKL exhibited a higher mutation frequency of FAT family genes, a more acute fulminant clinical course, and worse prognosis than ENKTL-BM, indicating that ANKL and ENKTL-BM can be distinguished both genetically and clinically. We expect the identified FAT1 gene mutations to serve as novel prognostic factors for ANKL.