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.
Highlights
Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with poor clinical outcome, characterized by the t(11;14)(q13;q32) translocation, resulting in overexpression of Cyclin D1
In germinal center B-cells and normal plasma cells hematopoietic cell kinase (HCK) was below the detection-threshold, whereas it was weakly expressed in memory B-cells (Fig. 1a)
Expression of HCK in MCL was comparable to Germinal Center (GC)-DLBCL and higher than in Waldenström’s Macroglobulinemia (WM), multiple myeloma (MM), or chronic lymphocytic leukemia samples (Fig. 1a)
Summary
Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with poor clinical outcome, characterized by the t(11;14)(q13;q32) translocation, resulting in overexpression of Cyclin D1. Advances in MCL therapy have improved patient prognosis, but due to primary and secondary resistance there is a high clinical need for novel therapeutic targets [1]. In Waldenström’s Macroglobulinemia (WM) and activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL) cells harboring the pathogenic MYD88-L265P mutation, mutant MYD88dependent HCK expression was observed and HCK knockdown reduces cell viability, implying that HCK targeting could be beneficial in patients with lymphomas with mutant MYD88 [8]. No MYD88 mutations have been reported in MCL, MYD88-regulatory toll-like receptors (TLRs) are upregulated and TLR stimulation supports cell proliferation and survival [9,10,11]. HCK controls proliferation and survival as well as integrin-mediated adhesion of MCL cells. Possibly in other lymphomas that do not harbor MYD88 mutations
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