Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome

Abstract

Cutaneous T-cell lymphoma (CTCL) is defined by infiltration of activated and malignant T cells in the skin. The clinical manifestations and prognosis in CTCL are highly variable. In this study, we hypothesized that gene expression analysis in lesional skin biopsies can improve understanding of the disease and its management. Based on 63 skin samples, we performed consensus clustering, revealing 3 patient clusters. Of these, 2 clusters tended to differentiate limited CTCL (stages IA and IB) from more extensive CTCL (stages IB and III). Stage IB patients appeared in both clusters, but those in the limited CTCL cluster were more responsive to treatment than those in the more extensive CTCL cluster. The third cluster was enriched in lymphocyte activation genes and was associated with a high proportion of tumor (stage IIB) lesions. Survival analysis revealed significant differences in event-free survival between clusters, with poorest survival seen in the activated lymphocyte cluster. Using supervised analysis, we further characterized genes significantly associated with lower-stage/treatment-responsive CTCL versus higher-stage/treatmentresistant CTCL. We conclude that transcriptional profiling of CTCL skin lesions reveals clinically relevant signatures, correlating with differences in survival and response to treatment. Additional prospective long-term studies to validate and refine these findings appear warranted.

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

“…Although the molecular pathogenesis of aggressive T-cell and NK cell malignancies remains unclear, ITK and RLK have been shown to be critical mediators of intracellular signaling that support the survival and growth of these malignancies (65)(66)(67). Our studies reveal that ITK-and RLK-based signaling in T-PLL can be blocked by PRN694, thereby starving these cells of an essential activation pathway.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…More recently, peripheral blood monocytes (and their progeny) were shown to support the growth of malignant T cells in vitro, confer resistant to chemotherapy, and promote tumor engraftment in immunodeficient mice [45]. Lymphoma-derived IL-10, upregulated in patients with advanced-stage disease poorly responsive to therapy [47], impairs the maturation of lymphoma-associated dendritic cells, rendering them immunologically incompetent, thus promoting escape from host antitumor immune surveillance. In addition, lymphoma-associated dendritic cells were observed to express the T-cell coinhibitory ligand B7-H1 (PD-L1, CD274), which directly inhibits the proliferation of tumor-specific T cells, but also indirectly impairs antitumor immunity by promoting the induction of suppressive regulatory T cells [48].…”

“…In patients with advanced-stage disease, and half of patients with limited-stage disease, a dramatic loss of TCR diversity was observed. Whether this observation may be explained by tumor-mediated suppression of nonmalignant T cells, diminished thymic output of naïve T cells and compensatory homeostatic expansion of oligoclonal peripheral T cells, or some other mechanism, is unknown [47]. As lymphopenia is an adverse prognostic factor in many hematologic malignancies [59][60][61][62][63][64], and undoubtedly contributes to the infectious complications observed in CTCL, improved understanding of the causative mechanism(s) leading to this dramatic loss of T-cell diversity may have significant therapeutic implications.…”

“…Shin et al performed a gene expression profiling analysis on lesional skin biopsy specimens obtained from 62 CTCL patients and identified three distinct gene expression clusters that were prognostically important [47], that were later confirmed by RT-PCR analysis [195]. The first cluster was associated with the upregulation of genes involved in T-cell activation, homing and tumor necrosis factor (TNF) signaling.…”

New molecular insights into peripheral T cell lymphomas

“…Indeed, several reports documented their positive activity in AITL cases (79)(80)(81)(82)(83)(84). More recently, a possible pathogenetic role of VEGF has been proposed for MF as well (85,86). Indeed, VEGF deregulation may be an early event in this disease.…”