Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma

Abstract

IntroductionCutaneous T-cell lymphomas (CTCL) are the most frequent primary lymphomas of the skin, with mycosis fungoides (MF) being the most prevalent clinical form. 1 In early disease stages, which can last several years, MF presents as flat erythematous skin patches resembling inflammatory diseases such as allergic contact dermatitis, eczema, or psoriasis. In later stages, MF lesions gradually form plaques and overt tumors and may disseminate to lymph nodes and internal organs. The early skin lesions contain numerous inflammatory cells, including a large quantity of T cells with a normal phenotype as well as a small population of T cells with abnormal morphology and a malignant phenotype. T cells with a malignant phenotype are characterized by epidermotropism and are preferentially present in the upper parts of the skin, whereas T cells with a normal phenotype primarily are detected in the lower portions of the dermis. The epidermal T cells are sometimes found in patterns of Pautrier microabscesses, which are collections of T cells adherent to dendritic processes of Langerhans cells. During disease development, the epidermotropism is gradually lost concomitant with an increase in malignant, and a decrease in nonmalignant, infiltrating T cells. The etiology of CTCL remains poorly understood, and occupational exposures, infectious agents, and genetic mutations have been proposed as etiological factors, but no evidence of causation has been provided. [2][3][4][5][6] However, already in early disease stages, the transcription factor nuclear factor-kappa B (NF-B) has been shown to be constitutively active in the malignant T cells of patients with CTCL where it promotes proliferation and cell survival. [7][8][9] The malignant T cells also show aberrant hyperactivation of the Janus kinase 3 (Jak3)/signal transducer and activator of transcription 3 (Stat3) pathway, which protects them from apoptosis and is a marker of resistance to therapy. [10][11][12][13] It has been hypothesized that the aberrant activation of NF-B and the Jak3/Stat3 pathway are key events in the development of CTCL. [7][8][9][10] Early diagnosis of CTCL has important consequences concerning therapeutic options and determination of prognosis. 14 Currently, it is primarily based on clinical observations and histologic examinations of cutaneous biopsies as well as additional laboratory tests such as analysis of T-cell receptor (TCR) clonality by polymerase chain reaction (PCR). Unfortunately, early diagnosis of CTCL has proven difficult because of the great clinical, pathologic, and histologic resemblance to benign inflammatory skin diseases and because inflammatory skin disorders can be associated with clonal TCR rearrangements. [15][16][17][18] In humans, the Src family kinases (SFKs) of nonreceptor protein tyrosine kinases classically consists of 8 members: c-Src, Fyn, Lck, c-Yes, Fgr, Hck, Lyn, and B-lymphoid kinase (Blk). 19 Blk is exclusively expressed in B cells and thymocytes but not in mature T cells. [20][21][22] Besides a role of Blk in B...

Ectopic expression of embryonic stem cell and other developmental genes in cutaneous T-cell lymphoma

“…TOX (Thymocyte selectionassociated high mobility group box) and EVA1 (Epithelial C-like antigen 1) are usually expressed in thymocyte development, but are subsequently downregulated in mature T cells, 25,26 while BLK (B-lymphoid kinase) and POU2AF are usually specific to B cells and should not be expressed in T cells. 27,28 PLS3 (Plastin 3) is an actin binding protein, which is also normally not expressed in T cells. 6,29 Our RT-PCR analysis confirms that BLK, POU2AF, TOX, EVA1, and PLS3 are expressed in CTCL lesional skin biopsies (Fig.…”

“…27 Importantly, BLK is constitutively active in malignant T cells and appears to be a bona fide oncogene which drives malignant T cell proliferation in vitro and tumor formation in vivo. 27,51 In addition, recent translational experimental work revealed that TOX expression, which is usually silenced in mature T cells, can be used as a robust prognostic and diagnostic marker for MF and SS, 52,53 while PLS3 actin binding protein, which is usually not expressed in T cells is consistently expressed in CTCL. 6,29,54,55 A growing body of literature documents that ectopic expression of these genes in CTCL is not a mere indication of deregulated cellular processes, but an important mechanism of tumorigenesis and cancer progression.…”

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

“…Cyclin upregulation, including cyclinD1, and loss of RB1 have also been described [94]. As gene-expression profiling and nextgeneration sequencing technologies are used, additional pathogenic pathways, including those involving transcription factors regulating T-cell differentiation [35,36], c-MYC [95,96], RAS/RAF/MEK signaling [97], among others [90,98], may be identified in subsets of CTCL.…”

COX-2-dependent PGE2 acts as a growth factor in mycosis fungoides (MF)

“…Total RNA was isolated using RNeasy Mini Kit (Qiagen, Ballerup, Denmark) according to the manufacturer's instructions and reverse transcriptase-PCR was performed as described elsewhere 17 (all reagents were from Invitrogen, Paisley, UK; Taq polymerase is from New England Biolabs, Danvers, MA, USA). Primers (Supplementary Figure 1) were designed with Primer3, v 0.4.0 software (Duke-NUS Graduate Medical School, Singapore) 18 and synthesized by Eurofins MWG GmbH (Martinsried, Germany).…”

“…17 Samples were analyzed on a FACSCalibur using CellQuestPro software (Becton Dickinson, Brøndby, Denmark).…”