Proposed model of TET2 loss-of-function mutations contributing to enhanced JAK/STAT pathway activation in NK-LGL leukemia. Different stages within the leukemogenesis of NK-LGL leukemia are depicted from top to bottom. The discovery of recurrent damaging TET2 mutations in NK-LGL leukemia cells refines the current disease concept with the functional hallmark of constitutive JAK/STAT pathway activation, which is observed in nearly all NK-LGL leukemias. Malignant evolution driven by chronic cytokine stimulation is further fueled by frequently observed activating mutations of STAT3. The work by Olson et al now adds a new key player to this mechanistic disease concept, namely TET2. The authors identified TET2 loss-of-function variants in 28% of NK-LGL leukemia patients, which was associated with a highly aberrant methylation pattern and distinct clinical phenotypes. They further identified a hypermethylation of genes encoding for negative regulators of JAK/STAT signaling (eg, PTPRD and PTPRN), strongly enriched in those patients with TET2 mutations. This suggests additional modes of JAK/STAT hyperactivation in NK-LGL leukemogenesis besides STAT3 gain-of-function mutations. *TET2 mutations are a known genetic hallmark in several myeloid malignancies (eg, myelodysplastic syndrome [MDS] and acute myeloid leukemia) and have lately been identified as constituents of a clonal hematopoiesis of indeterminate potential.^7-9  Recently, Pastoret et al³  also observed concomitant TET2 mutations in the myeloid compartment of NK-LGL patients, proposing that precursor lesions are already present in hematogenic progenitors. Of note, Olson et al could not detect such TET2 lesions in non-NK PBMCs and did not find an elevated prevalence of myeloid neoplasms in TET2-mutated NK-LGL leukemias. mut, mutated; WT, wild type.