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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| Vydané v: | Leukemia Ročník 35; číslo 3; s. 881 - 886 |
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| Hlavní autori: | , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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01.03.2021
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| Abstract | 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. |
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| AbstractList | 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. 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.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. |
| Audience | Academic |
| Author | Kersten, Marie-José Minderman, Marthe Spaargaren, Marcel Lantermans, Hildo C. Kuil, Annemieke Pals, Steven T. |
| Author_xml | – sequence: 1 givenname: Hildo C. surname: Lantermans fullname: Lantermans, Hildo C. organization: Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Lymphoma and Myeloma Center Amsterdam – LYMMCARE – sequence: 2 givenname: Marthe surname: Minderman fullname: Minderman, Marthe organization: Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Lymphoma and Myeloma Center Amsterdam – LYMMCARE – sequence: 3 givenname: Annemieke surname: Kuil fullname: Kuil, Annemieke organization: Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Lymphoma and Myeloma Center Amsterdam – LYMMCARE – sequence: 4 givenname: Marie-José surname: Kersten fullname: Kersten, Marie-José organization: Lymphoma and Myeloma Center Amsterdam – LYMMCARE, Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam – sequence: 5 givenname: Steven T. surname: Pals fullname: Pals, Steven T. organization: Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Lymphoma and Myeloma Center Amsterdam – LYMMCARE – sequence: 6 givenname: Marcel orcidid: 0000-0002-3135-5109 surname: Spaargaren fullname: Spaargaren, Marcel email: marcel.spaargaren@amsterdamumc.nl organization: Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Lymphoma and Myeloma Center Amsterdam – LYMMCARE |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32591642$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1016/j.bbadis.2016.11.013 10.1182/blood-2013-02-482125 10.1182/blood-2011-11-390989 10.1126/scitranslmed.3004387 10.1006/bbrc.1999.1379 10.1182/blood-2014-12-619163 10.1182/blood-2015-10-673145 10.1182/blood-2016-01-695098 10.1128/MCB.7.6.2276 10.1002/hon.2251 10.1074/jbc.M305783200 10.1074/jbc.275.19.14615 10.1093/carcin/bgp206 10.1002/cncr.27792 10.1371/journal.pone.0153823 |
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| Snippet | Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma subtype arising from naïve B cells. Although novel therapeutics have improved patient... |
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| Title | Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma |
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