Patient samples resistant to ALK TKI show downregulation of PTPN1 and PTPN2 and upregulation of SHP2. (A) Representative hematoxylin-eosin and immunohistochemistry stainings of ALK, CD30, PTPN1, and PTPN2 in 1 ALK⁺ case expressing low PTPN1 and low PTPN2 (top) and 1 ALK⁺ ALCL case expressing high PTPN1 and high PTPN2 (bottom). Tumor cells are identified by ALK and CD30 stainings. High expression was determined by an H score >200. Scale bar, 100 μm. (B) Percentage of cases with high PTPN1 or PTPN2 protein expression of PTPN1 and PTPN2 evaluated by immunohistochemistry in human T-cell lymphoma subtypes: ALK⁺ ALCL (n = 30), ALK⁻ ALCL (n = 18), AITL (n = 10), and peripheral T-cell lymphoma (n = 10). High expression was determined by an H score >200. (C) RNA-seq data from chemotherapy-relapsed/refractory (n = 2) and ALK TKI–resistant (n = 2) patients to evaluate mRNA expression of PTPN1, PTPN2, and PTPN11 (SHP2). ALK mutation status was analyzed by sequencing following a biopsy of relapsed lymphoma samples. The 2 patients that relapsed after chemotherapy showed WT ALK. Of the 2 patients relapsed during ALK TKI, 1 patient was WT, and 1 patient carried the L1196M mutation in ALK. See supplemental Figure 12 for treatment details. CPM, counts per million.