The Use of Transcriptional Profiling to Improve Personalized Diagnosis and Management of Cutaneous T-cell Lymphoma (CTCL)

Abstract

Purpose While many Mycosis Fungoides (MF) patients presenting with stage I disease enjoy an indolent disease course and normal life expectancy, about 15-20% of them progress to higher stages, and most ultimately succumb to their disease. Currently, it's not possible to predict which patients will progress and which patients will have a stable disease. Previously, we conducted microarray analyses with RT-PCR validation of gene expression in biopsy specimens from 60 stage I-IV CTCL patients, identified three distinct clusters based upon transcription profile and correlated our molecular findings with 6 years of clinical follow up. Experimental Design We test by RT-PCR within our prediction model the expression of ∼240 genes that were previously reported to play an important role in CTCL carcinogenesis. We further extend the clinical follow up of our patients to 11 years. We compare the expression of selected genes between MF/Sézary Sydrome and benign inflammatory dermatoses that often mimic this cancer. Results Our findings demonstrate that 52 out of the ∼240 genes can be classified into cluster 1-3 expression patterns and such expression is consistent with their suggested biological roles. Moreover, we determined that 17 genes (CCL18, CCL26, FYB, T3JAM, MMP12, LEF1, LCK, ITK, GNLY, IL2RA, IL-26, IL-22, CCR4, GTSF1, SYCP1, STAT5A, TOX) are able to both identify patients who are at risk of progression and also distinguish MF/SS from benign mimickers. Conclusions This study, combined with other gene expression analyses, prepares the foundation for the development of personalized molecular approach towards diagnosis and treatment of CTCL.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…Enhanced STAT5 signaling was also linked to overexpression of oncogenic miR-155 in CTCL [86], associated with downregulation of tumor-suppressive miR-22 [87], or enhanced disease progression caused by Lymphotoxin-α-dependent lymphangiogenesis [88]. STAT5-dependent CD80 expression was also linked to resistance to Vorinostat and risk of disease progression in PTCL [84,89,90]. …”

Tumor-associated M2 macrophages in mycosis fungoides acquire immunomodulatory function by interferon alpha and interferon gamma

“…Notably, we identified several genes that were previously reported to correlate with CTCL biological activities (CCL7, CCL17, CCL18, CCL22, CCL26 and CXCL12) [8,9,[13][14][15]. Moreover, among the upregulated MMP-related genes, the mRNA expression of MMP12, which was previously correlated with the risk of progression of MF [8], was highly upregulated (Fig. 1). 3.2.…”

“…These in vitro data suggested that IL-4 polarizes macrophages into type 2 (M2) macrophages. To further analyze the M2 differentiation in macrophages by the stimulation of IL-4, we performed DNA microarray analysis, which suggested that monocyte-derived macrophages could obtain the ability by IL-4 stimulation to produce chemokines that had been correlated with CTCL biological activities [8,9,[13][14][15]. These reports suggest that chemokines derived from TAMs stimulated by IL-4 play a crucial role in the progression of advanced MF.…”

“…To validate the quantitative RT-PCR results obtained by using M2 macrophages treated with IFNs, we used ELISA to examine chemokine protein production by M2 macrophages 48 h after stimulation with IFN-a2a or IFN-g, especially focusing on chemokines (CCL7, CCL17, CCL18, CCL22, CCL26, CXCL10, CXCL11 and CXCL12) previously reported to contribute to the formation and progression of MF [8,9,[13][14][15]. Consistent with the mRNA expression, the secretion of CXCL10 and CXCL11 protein was significantly augmented by IFN-a2a or IFN-g stimulation, while the secretion of CCL17 and CCL18 protein was significantly decreased compared to untreated cells.…”

“…In cutaneous T-cell lymphoma (CTCL), macrophage-related chemokines and angiogenic factors produced by TAMs have crucial roles in tumor formation in the lesional skin of MF [8,9]. In addition, we have also reported that the stromal factor of MF, periostin, could stimulate macrophages to produce chemokines that affect the formation of MF [4].…”