Large granular lymphocyte leukemia (LGL L) includes T-cell LGL L and chronic lymphoproliferative disorders of NK cells (CLPD-NK) with indolent clinical course. STAT signaling system has been shown to play a crucial role in LGL L. We reported somatic mutations in the STAT3 gene in LGL L, which is associated with pure red cell aplasia among an Asian cohort. Since STAT5b mutations in LGL leukemia had also been discovered, we investigated mutations in STAT5b gene in Japanese patients with LGL L. Among 28 T-LGL L and 11 CLPD-NK, N642H and Y665F activating mutations in the SH2 domain of the STAT5b were found in 3 and 1 patient (pt)s, respectively, by direct sequencing, which was confirmed with the corresponding allele-specific (AS) PCR. The frequencies of STAT5b mutations in T-LGL L and CLPD-NK were 14.3% and 0%, respectively. Median age of the 4 pts was 76.5 years and mild neutropenia was recognized in 2pts, but no one was anemic. None of them showed apparent aggressive clinical courses, in contrast to previous reported cases (Rajala HLM et al, BLOOD 2013). Interestingly, STAT5b mutations were associated with a unique phenotype of LGL L with CD4+CD56+TCR αβ type (P = 0.0001). The mutations of STAT5b and STAT3 were mutually exclusive. In contrast to STAT3 mutation-positive patients, among whom significant part of the patients possessed STAT3-mutated subclones only detected with AS-PCR, no pt was identified to be positive for STAT5b mutation only with AS-PCR. We also investigated STAT5b mutations in 29 Chinese patients cohort with T cell LGL L by AS-PCR for N642H and Y665F, and found that no patient was positive for the mutations. Our results indicate that the STAT5b gene is mutated in T-LGL L, which would affect a specific immunophenotype of LGL. STAT5b and STAT3 mutations have significant but distinct contributions to the pathobiology of LGL L and STAT5b-mutated LGL L may consist a unique subtype of LGL L.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.