Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma subtype arising from naïve B cells. Although novel therapeutics have improved patient prognosis, drug resistance remains a key problem. Here, we show that the SRC-family tyrosine kinase hematopoietic cell kinase (HCK), which is primari...

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Vydáno v:	Leukemia Ročník 35; číslo 3; s. 881 - 886
Hlavní autoři:	Lantermans, Hildo C., Minderman, Marthe, Kuil, Annemieke, Kersten, Marie-José, Pals, Steven T., Spaargaren, Marcel
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.03.2021 Nature Publishing Group
Témata:	13/1 13/109 13/2 13/31 13/89 38 38/39 38/61 42/41 631/67/1059/602 631/67/1990/291/1621/1915 631/67/395 82/29 82/80 96 Apoptosis Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cancer Research Care and treatment Cell cycle Cell proliferation Cell receptors Critical Care Medicine Development and progression Drug resistance Extracellular matrix Gene expression Genetic aspects Hck protein Health aspects Hematology Humans Intensive Internal Medicine Kinases Letter Lymphocytes B Lymphoma Lymphoma, Mantle-Cell - genetics Lymphoma, Mantle-Cell - metabolism Lymphoma, Mantle-Cell - pathology Mantle cell lymphoma Medical prognosis Medicine Medicine & Public Health Microenvironments MyD88 protein Non-Hodgkin's lymphoma Oncology Phosphotransferases Prognosis Protein-tyrosine kinase Proto-Oncogene Proteins c-hck - genetics Proto-Oncogene Proteins c-hck - metabolism Signal Transduction Src protein Stromal cells Survival Therapeutic targets Toll-like receptors Tumor Microenvironment Tyrosine Netherlands
ISSN:	0887-6924, 1476-5551, 1476-5551
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Popis
Shrnutí:	Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma subtype arising from naïve B cells. Although novel therapeutics have improved patient prognosis, drug resistance remains a key problem. Here, we show that the SRC-family tyrosine kinase hematopoietic cell kinase (HCK), which is primarily expressed in the hematopoietic lineage but not in mature B cells, is aberrantly expressed in MCL, and that high expression of HCK is associated with inferior prognosis of MCL patients. HCK expression is controlled by the toll-like receptor (TLR) adaptor protein MYD88 and can be enhanced by TLR agonists in MCL cell lines and primary MCL. In line with this, primary MCL with high HCK expression are enriched for a TLR-signaling pathway gene set. Silencing of HCK expression results in cell cycle arrest and apoptosis. Furthermore, HCK controls integrin-mediated adhesion of MCL cells to extracellular matrix and stromal cells. Taken together, our data indicate that TLR/MYD88-controlled aberrant expression of HCK plays a critical role in MCL proliferation and survival as well as in retention of the malignant cells in the growth- and survival-supporting lymphoid organ microenvironment, thereby contributing to lymphomagenesis. These novel insights provide a strong rationale for therapeutic targeting of HCK in MCL.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Correspondence-1 content type line 23
ISSN:	0887-6924 1476-5551 1476-5551
DOI:	10.1038/s41375-020-0934-6