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High STAT5A activity promotes CD8+ T-cell neoplasia
and STAT5B nuclear staining intensities across PTCL enti- ties (Figure 6D, Online Supplementary Figure S6G).
In brief, patient-derived PTCL samples displayed STAT5 upregulation and enhanced intensity of STAT5A/B nuclear staining, pointing to an important role of STAT5 in various PTCL subsets. These findings establish elevat- ed expression of STAT5A/B across human PTCL entities, which we finally set out to target pharmacologically.
Proliferation of peripheral T-cell lymphoma cells is highly sensitive to targeted JAK/STAT pathway therapy
Primary cultures of cS5Ahi CTL were cytokine-depen- dent and hypersensitive to IL-2, IL-4 and IL-7. This indi- cates higher cytokine-induced proliferation of cS5Ahi compared to wt cells (Figure 7A, Online Supplementary
A
Figure S7A), also reflected by the longer pYSTAT5 persist- ence after IL-2 withdrawal (Figure 7B, Online Supplementary Figure S7B). Results from our mouse mod- els32 and recent literature30,52 indicate that inhibition of STAT5 signaling may represent a therapeutic option in PTCL patients. We investigated the effects of the Food and Drug Administration-approved JAK1/2 inhibitor rux- olitinib and JAK1/2/3 inhibitor tofacitinib38, as cS5AF depends on upstream cytokine signaling, as well as the STAT5 inhibitor AC-3-19, which was described to inhibit pYSTAT5 activation and downstream target genes.39,53 In the presence of IL-2, cS5Ahi mice-derived CTL cells were treated with increasing concentrations of these JAK and STAT5 inhibitors, which led to decreased STAT5 activa- tion and cell viability (Figure 7C, Online Supplementary
C
Figure 6. Enhanced STAT5 expression and activity in peripheral T-cell lymphoma, not otherwise specified. (A) STAT5A (top) and STAT5B (bottom) stain- ing of representative non-dis- eased human lymph nodes (hLN, n=4) and peripheral T-cell lymphoma, not otherwise speci- fied (PTCL, NOS) cases (n=8) with nuclear STAT5A/B staining intensity scoring. Scale bars indi- cate 100 or 50 μm. (B) Summary of scoring of nuclear STAT5A (top) and STAT5B (bot- tom) staining intensity ranging from 1 (low) to 4 (high). (C) STAT5A (left) and STAT5B (mid- dle) mRNA levels of non-dis- eased hLN (n=4) vs. PTCL, NOS lymphoma tissue (n=18, STAT5A P=0.016, STAT5B P=0.11, unpaired t-test). Mean STAT5A or STAT5B expression in hLN was normalized to 1. (D) Statistical summary of nuclear STAT5A (left) and STAT5B (right) staining intensity, classified as weakly positive, positive and strongly positive, of 35 PTCL, NOS, 14 angioimmunoblastic T-cell lym- phoma (AITL), 7 cutaneous T-cell lymphoma (CTCL), 6 mycosis fungoides (MF), and 5 control samples spotted on a tissue microarray.
D
B
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