Proliferation and survival signals in chronic LGL diseases. (A) Constitutive STAT3 activation in leukemic cells. (Ai) Western blot analysis in leukemic cells from 4 T-LGL patients (2 mutated and 2 wild-type), 4 CLPD-NK patients (2 mutated and 2 wild-type), and a control. (Aii) Aberrant intracellular pSTAT3 signal (brown) has been also detected in paraffin sections from bone marrow biopsy samples of STAT3-mutant and nonmutant cases of T and NK origin. Previous immunohistochemical staining with CD8, surface CD3, and CD2 defined the cell lineage of the lymphocyte infiltration. Positive double staining with anticytoplasmic CD3 (pink) and pSTAT3 (brown) showed aberrant pSTAT3 signal in the infiltrating lymphoid compartment. Finally, a healthy donor tonsil sample shows no brown nuclei in cCD3-positive cells. (B) STAT3 pathway-related genes deregulated. (Bi) Heat map reflecting color-coded expression levels from a set of genes known to be regulated by STAT3 (columns) in purified T-LGL cells from 3 patients and control samples (rows). (Bii) Pie chart depicting whole genome expression in the 3 T-LGL leukemia patients and overlapping circles showing a high degree of coincidences in deregulated genes in mutated and nonmutated patients. (Ciii) Histograms of whole genome expression levels separated by pathways, exposing a predominance of deregulation in apoptosis and cell death, both in mutated and nonmutated patients. Up-regulated pathway genes are shown in pink (top panel) and down-regulated pathway genes in green (bottom panel).