Leukemic N642H^NK/NK NK cells display molecular features of patients with NK-cell leukemia harboring STAT5B GOF mutations. RNA-Seq data of NK cells from Cre neg, GFP^NK/NK, STAT5B^NK/NK, nondiseased and diseased N642H^NK/NK mice and patients with NK-cell leukemia. (A) Principal component analysis of RNA-Seq data of control (peripheral blood mononuclear cells), B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-cell acute lymphoblastic leukemia (T-ALL), patients with NK-cell leukemia: without JAK/STAT mutations (NK-cell leukemia, n = 44), with mutated STAT3 (NK-cell leukemia [STAT3 mut], n = 16), with mutated JAK1 (NK-cell leukemia [JAK1 mut], n = 1), or with STAT5B GOF mutations (NK-cell leukemia [STAT5B GOF], n = 3). One patient with STAT5B GOF harbors a STAT5B^N642H, 1 harbors a STAT5B^Q706L, and 1 patient harbors a STAT5B^Y665F and a STAT5B^V712E comutation. (B) Venn diagram illustrating common DEGs from the comparisons diseased N642H^NK/NK (n = 8) vs control (GFP^NK/NK or Cre neg mice; n = 5) (adjusted P < .1) and NK-cell leukemia (STAT5B GOF) (n = 3) vs NK-cell leukemia (n = 44) (FDR < 0.1). This analysis considered exclusively DEGs with available human-mouse orthologues. (C) Heat map illustrating expression of the commonly regulated DEGs from the comparisons: diseased N642H^NK/NK (n = 8) vs control (n = 5) and NK-cell leukemia (STAT5B GOF) (n = 3) vs NK-cell leukemia (n = 44). (D) Venn diagram illustrating significant (FDR < 0.1) hallmark pathways from the comparisons diseased N642H^NK/NK (n = 8) vs control (n = 5) and NK-cell leukemia (STAT5B GOF) (n = 3) vs NK-cell leukemia (n = 44). (E) Quantification of the normalized enrichment score of the 13 common hallmark pathways identified (D). FDR, false discovery rate; GSEA, gene set enrichment analysis.