B-lymphoid tyrosine kinase (Blk) is an oncogene and a potential target for therapy with dasatinib in cutaneous T-cell lymphoma (CTCL)

Petersen, David L.; Krejsgaard, Thorbjørn; Berthelsen, Jens; Fredholm, Simon; Willerslev-Olsen, Andreas; Sibbesen, Nina A.; Bonefeld, Charlotte M.; Andersen, Mads Hald; Francavilla, Chiara; Olsen, Jørgen; Hu, Tengpeng; Zhang, M; Wasik, Mariusz A.; Geisler, Carsten; Woetmann, Anders; Ødum, Niels

doi:10.1038/leu.2014.192

Cited by 48 publications

(41 citation statements)

References 12 publications

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“…Several studies have demonstrated aberrant tyrosine kinase signalling in NHLs and these observations have led to the exploration of tyrosine kinase inhibitors in NHLs (Brave et al , ; Dickerson et al , ; Heldin, ; Petersen et al , ). This is the first clinical trial of dasatinib in refractory NHL, where we observed an ORR of 32% and a clinical benefit rate of 52%, with a median PFS of 3 months and OS of 22·4 months.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II study of dasatinib and exploratory genomic analysis in relapsed or refractory non‐Hodgkin lymphoma

et al. 2018

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Summary Relapsed or refractory non‐Hodgkin lymphomas (NHLs) often carry poor prognosis and pose management challenges. We evaluated the safety and efficacy of dasatinib, a broad‐spectrum multi‐kinase inhibitor in relapsed/refractory NHL with correlative genomic analysis in a Phase I/II trial. The study included 33 patients with various sub‐types of NHL who had received at least one prior therapy. The most common sub‐types were diffuse large B‐cell lymphoma (24%), follicular lymphoma, grade 1/2 (21%) and peripheral T‐cell lymphoma not otherwise specified (PTCL‐NOS; 21%). Most patients were heavily pre‐treated, including 42% with more than four prior therapies, 67% with rituximab exposure and 24% with prior autologous transplant. In this cohort, dasatinib showed modest activity in evaluable patients with an objective response rate of 29% (7/24) and clinical benefit rate of 71% (17/24). In 32 patients with outcome data, median progression‐free survival was 3 months and median overall survival was 22·4 months. There were two patients with sustained complete responses, both with PTCL‐NOS histology. The side effect profile was consistent with prior studies, with pleural effusion being the most common non‐haematological toxicity. Exploratory genomic analysis showed two cases of PTCL‐NOS with sustained response had a common mutation in LRRK2 and high prevalence of FOXO1 mutation in relapsed/refractory follicular lymphoma.

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Section: Discussionmentioning

confidence: 99%

Phase I/II study of dasatinib and exploratory genomic analysis in relapsed or refractory non‐Hodgkin lymphoma

et al. 2018

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“…EVA1 (also known as MPZL2), another poor prognosis marker, is expressed early on in the thymus, but then is strongly downregulated during thymocyte developmental progression(38). Also, previous work suggested that a B cell specific gene, B-lymphoid kinase or 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 (39). In this study we confirm the expression of the aforementioned genes in CTCL and demonstrate that another B cell-specific transcriptional factor POU2AF1 is expressed in poor prognosis cluster 1 patients.…”

Section: Discussionmentioning

confidence: 99%

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

Litvinov

Netchiporouk

Cordeiro

et al. 2015

Clinical Cancer Research

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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.

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“…Moreover, gene knockdown experiments revealed that Blk promoted the proliferation of malignant T cells in CTCL patients [30] while another study suggested that murine Blk also has tumor-suppressive functions depending on the specific cellular context [29]. Peterson et al [31] in a recent study of Blk in CTCL provided evidence that the active form of human Blk is able and sufficient to confer cytokine independence to cytokine-dependent lymphoid cells while promoting tumor growth in vivo and supporting growth of lymphoid cells in vitro.…”

Section: Cutaneous T-cell Lymphoma (Ctcl)mentioning

confidence: 99%

Proteomic Approaches to Biomarker Discovery in Cutaneous T-Cell Lymphoma

et al. 2016

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Cutaneous T-cell lymphoma (CTCL) is the most frequently encountered type of skin lymphoma in humans. CTCL encompasses multiple variants, but the most common types are mycosis fungoides (MF) and Sezary syndrome (SS). While most cases of MF run a mild course over a period of many years, other subtypes of CTCL are very aggressive. The rapidly expanding fields of proteomics and genomics have not only helped increase knowledge concerning the carcinogenesis and tumor biology of CTCL but also led to the discovery of novel markers for targeted therapy. Although multiple biomarkers linked to CTCL have been known for a relatively long time (e.g., CD25, CD45, CD45RA, and CD45R0), compared to other cancers (lymphoma, melanoma, colon carcinoma, head and neck cancer, renal cancer, and cutaneous B-cell lymphoma), information about the antigenicity of CTCL remains relatively limited and no dependable protein marker for CTCL has been discovered. Considering the aggressive nature of some types of CTCL, it is necessary to identify circulating molecules that can help in the early diagnosis, differentiation from inflammatory skin diseases (psoriasis, nummular eczema), and aid in predicting the prognosis and evolution of this pathology. This review aims to bring together some of the information concerning protein markers linked to CTCL, in an effort to further the understanding of the convolute processes involved in this complex pathology.

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B-lymphoid tyrosine kinase (Blk) is an oncogene and a potential target for therapy with dasatinib in cutaneous T-cell lymphoma (CTCL)

Cited by 48 publications

References 12 publications

Phase I/II study of dasatinib and exploratory genomic analysis in relapsed or refractory non‐Hodgkin lymphoma

Phase I/II study of dasatinib and exploratory genomic analysis in relapsed or refractory non‐Hodgkin lymphoma

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

Proteomic Approaches to Biomarker Discovery in Cutaneous T-Cell Lymphoma

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