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

Abstract

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.

Keywords: FAT1; Aggressive NK-cell Leukemia; Bone marrow neoplasms; Extranodal NK/T-cell lymphoma; Next generation sequencing.

Fig. 1

Alterations identified by targeted sequencing. Among 282 targeted genes, alterations were detected in 142 genes. Of these, 74 genes with high frequencies of alterations are visualized in this oncoplot. The remaining part of the oncoplot can be found in Supplementary Figure S1 online. Genes are listed in descending order of alteration frequency, and their categorization is based on their biological functions or signaling pathways. Diagonally split dual-colored cells represent the presence of two different types of alterations in one sample. CNAs and cytogenetic abnormalities are shown at the bottom of the oncoplot. Each column represents a study subject. Abbreviations: ANKL, aggressive NK-cell leukemia; ENKTL-BM, extranodal NK/T-cell lymphoma with bone marrow involvement; CNA, copy number alteration.

Fig. 2

Copy number alterations identified by sequencing. The order of the study subjects (x-axis) is the same as in Fig. 1. CNAs are listed in chromosomal order, with key genes at each locus indicated alongside. Abbreviations: ANKL, aggressive NK-cell leukemia; ENKTL-BM, extranodal NK/T-cell lymphoma with bone marrow involvement; CNA, copy number alteration.

Fig. 3

Kaplan–Meier survival curves of patients with ANKL and ENKTL-BM. P < 0.05 was considered statistically significant for the Log-rank test. Abbreviations: ANKL, aggressive NK-cell leukemia; ENKTL-BM, extranodal NK/T-cell lymphoma with bone marrow involvement.

Fig. 4

Kaplan–Meier survival curves of ANKL (n = 15) patients according to mutations in (A) FAT1, (B) FAT3, (C) FAT4, (D) FAT family, (E) ARID1A, and (F) ARID family. FAT family included FAT1, FAT3, and FAT4. ARID family included ARID1A, ARID1B, and ARID2. Survival analyses of patients with ARID1B and ARID2 mutations could not be performed due to the small number of samples. P < 0.05 was considered statistically significant for the Log-rank test. Abbreviations: mut, mutated; WT, wild type.