TY - JOUR

T1 - Loss of SHP-1 tyrosine phosphatase expression correlates with the advanced stages of cutaneous T-cell lymphoma

AU - Witkiewicz, Agnieszka

AU - Raghunath, Puthiyaveettil

AU - Wasik, Agnieszka

AU - Junkins-Hopkins, Jacqueline M

AU - Jones, Dan

AU - Zhang, Qian

AU - Odum, Niels

AU - Wasik, Mariusz A

N1 - Keywords: DNA (Cytosine-5-)-Methyltransferase; Gene Silencing; Humans; Immunohistochemistry; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Protein Tyrosine Phosphatase, Non-Receptor Type 6; STAT3 Transcription Factor; Skin Neoplasms

PY - 2007

Y1 - 2007

N2 - Cutaneous T-cell lymphoma (CTCL) comprises distinct and often progressive stages of skin involvement by patches, plaques, and tumors. We have previously demonstrated that CTCL-derived malignant T-cell lines display loss of a tumor suppressor SHP-1 tyrosine phosphatase because of epigenetic silencing of its gene. The silencing is induced by an activated phosphorylated (p)-STAT3 transcription factor in cooperation with DNA methyltransferase 1 (DNMT1), the key member of the epigenetic gene silencing machinery. To determine at which stage of CTCL the loss of SHP-1 occurs and how it correlates with the expression of (p)-STAT3 and DNMT1, we examined by immunohistochemistry 47 formalin-fixed skin biopsies from various stages of CTCL. Six pairs of the biopsies were obtained before and after CTCL progression at the patch or plaque and tumor stage, respectively. In 5 of these pairs, we identified loss of SHP-1 expression in atypical lymphocytes at the tumor stage; less prominent SHP-1 loss was noted in 3 biopsies from the earlier stage. The SHP-1 loss was also observed in 5 of 6 tumor, 12 of 18 plaque, and only 2 of 11 patch stages in patients with single biopsies. The expression of (p)-STAT3 and DNMT1 could be identified in almost all cases in at least a subset of the lesional cells. Based on these findings, we postulate that expression of (p)-STAT3 and DNMT1 occurs at the early stages of CTCL, and that this expression alone seems insufficient to induce loss of SHP-1 expression. In turn, SHP-1 loss correlates with, and may contribute to, progression of CTCL.

AB - Cutaneous T-cell lymphoma (CTCL) comprises distinct and often progressive stages of skin involvement by patches, plaques, and tumors. We have previously demonstrated that CTCL-derived malignant T-cell lines display loss of a tumor suppressor SHP-1 tyrosine phosphatase because of epigenetic silencing of its gene. The silencing is induced by an activated phosphorylated (p)-STAT3 transcription factor in cooperation with DNA methyltransferase 1 (DNMT1), the key member of the epigenetic gene silencing machinery. To determine at which stage of CTCL the loss of SHP-1 occurs and how it correlates with the expression of (p)-STAT3 and DNMT1, we examined by immunohistochemistry 47 formalin-fixed skin biopsies from various stages of CTCL. Six pairs of the biopsies were obtained before and after CTCL progression at the patch or plaque and tumor stage, respectively. In 5 of these pairs, we identified loss of SHP-1 expression in atypical lymphocytes at the tumor stage; less prominent SHP-1 loss was noted in 3 biopsies from the earlier stage. The SHP-1 loss was also observed in 5 of 6 tumor, 12 of 18 plaque, and only 2 of 11 patch stages in patients with single biopsies. The expression of (p)-STAT3 and DNMT1 could be identified in almost all cases in at least a subset of the lesional cells. Based on these findings, we postulate that expression of (p)-STAT3 and DNMT1 occurs at the early stages of CTCL, and that this expression alone seems insufficient to induce loss of SHP-1 expression. In turn, SHP-1 loss correlates with, and may contribute to, progression of CTCL.

U2 - 10.1016/j.humpath.2006.09.012

DO - 10.1016/j.humpath.2006.09.012

M3 - Journal article

C2 - 17239936

VL - 38

SP - 462

EP - 467

JO - Human Pathology

JF - Human Pathology

SN - 0046-8177

IS - 3

ER -