Live and let (MPN cells) die!

and ample material for future investigations. Jerez et al focused on the SH2 domain in their search for mutations. 1 However, some of the gain-of-function STAT3 mutations found in hepatocellular carcinoma are outside this domain, 4 suggesting that all domains of the STAT3 gene should also be closely inspected before we call them truly wild-type. Detailed sequence analysis could also solve the current paradox that neither laboratory findings nor the overall survival seem to distinguish between patients with wild-type and mutant STAT3 SH2 domains. Now that mutations in the STAT3 gene in LGL are identified, the next step is to explore the functional consequence of these alterations in CD8 ϩ T cells and NK cells. The transduc-tion of STAT3 mutants identified in LGL, which are presumably gain-of-function mutants , and, as a control, from Job syndrome patients, which represent loss-of-function or hypomorphic mutants, into CD8 T cells/NK cells from healthy donors should educate us on the effect these variants have on gene expression , proliferation, and survival on cytokine withdrawal, and leukemic behavior in the form of extended survival in a xenogenic mouse model. Furthermore, such studies should uncover differences in the way T cells and NK cells handle STAT3 mutants. Lastly, although T-LGL is characterized by the expansion of CD57 ϩ CD8 ϩ T cells, 2 we observed that the LGL clone is represented in both CD57 ϩ and in CD57 Ϫ fractions. 5,6 Indeed , CD57 ϩ cells lacked proliferative capacity , 7 but were readily generated from sorted CD57 Ϫ LGL cells. 5 With the recent discovery of a stem cell memory T cell (T SCM), 8 a burning question is whether the T-LGL clone originates in early memory cells and carries the mutant STAT3 gene. Such a finding would refocus the need to target STAT3 inhibitors on the true LGL stem cell. Conflict-of-interest disclosure: The author declares no competing financial interests. ■ REFERENCES 1. Jerez A, Clemente MJ, Makishima H, et al. STAT3 mutations unify the pathogenesis of chronic lymphoprolifera-tive disorders of NK cells and T-cell large granular lympho-cyte leukemia. activating STAT3 in human inflammatory hepatocellular adenomas. Barrett AJ. Large granular lymphocyte leukaemia is characterized by a clonal T-cell receptor rearrangement in both memory and effector CD8(ϩ) lympho-cyte populations. 6. Melenhorst JJ, Eniafe R, Follmann D, et al. T-cell large granular lymphocyte leukemia is characterized by massive TCRBV-restricted clonal CD8 expansion and a generalized overexpression of …