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  • CCR is another chemokine receptor that is upregulated in CLL


    CCR7 is another chemokine receptor that is upregulated in CLL [3], [61], [71], [96] and is believed to play a role in enabling cell entry into lymph nodes [97]. Higher mRNA and protein expression of CCR7 has been observed in unmutated compared to mutated IGHV CLL [46] and increased expression has been correlated with disease stage [76] and lymphadenopathy [46]. ZAP-70 has been shown to upregulate CCR7 via an ERK1/2-dependent mechanism that is also believed to regulate CXCR4 and CXCR5 [98]. The atypical chemoattractant GPCR CCRL2 (also known as CRAM) surface protein is expressed on CLL cells and is believed to regulate CCR7- and CCL19-mediated cell responses [99]. Finally, CCR7 and CXCR4 function together to upregulate matrix metallopeptidase 9 (MMP-9) to enable CLL cell migration [100]. Treatment of CLL patients with anti-CCR7 monoclonal antibody has shown promise in mice and humans [101]. Many chemokine receptors have varied expression in CLL based on the subtype of CLL being studied and the method used to identify the receptor. Similar to CXCR5, CCR6 protein expression was significantly reduced in poor-prognosis del 17p/11q CLL compared to normal CLL [93]. In addition, gene expression profiling showed that CCR6 was downregulated compared to memory gpcr signaling [61] while studies have reported a range from 23 to 100% of CLL/SLL cases that were positive for CCR6 [3], [10], [72], [102]. CX3CR1 protein was found to be present in 27–100% of CLL/SLL cases [103], [104] and CX3CR1 gene expression was higher in IGHV mutated than unmutated patients [105]. Interestingly, binding of CX3CL1 to CX3CR1 resulted increased CXCR4 MFI on CLL cells in vitro [104]. CCR1 and CXCR2 have both been detected in CLL/SLL. 4/35 (11%) cases of CLL/SLL were positive for CCR1 via an IHC analysis [14] and 9/13 CLL patient samples were positive for CCR1 as measured by flow cytometry [72]. Conversely, CXCR2 was detected in 7/51 (14%) CLL cases via IHC [106] but 0/13 (0%) cases via flow cytometry [72].
    Mantle cell lymphoma Among Non-Hodgkin\'s lymphoma (NHL) subtypes, the endocannabinoid system has been most extensively described in MCL due to the consistent overexpression of the cannabinoid receptors CNR1 and CNR2 in malignant tissue compared to normal B lymphocytes [51], [107], [108], [109], [110], [111], [112]. In a study of 107 MCL tissue samples, CNR1 and CNR2 mRNA was overexpressed in 98% and 100% of samples, respectively, and the degree of overexpression informed clinical factors [113]. CNR1 was significantly more strongly expressed in conventional MCL compared to indolent MCL [114] and significant associations were found between low CNR1 expression and lymphocytosis and leukocytosis as well as between high CNR2 expression and anemia [113]. Gene expression profiling of MCL primary tissue and cell lines compared to normal B cells found upregulation of CNR1 and the adrenergic receptor ADRB2 along with downregulation of the chemokine receptors CXCR5 and CCR6 and purinergic receptor P2RY11 in MCL although further flow cytometry found variable expression of the chemokine receptors [115], [116]. Therapeutic efforts to treat MCL primary cells and cell lines with cannabinoids resulted in decreased cell viability along with upregulated ceramide synthesis, apoptosis and cell death in MCL but not normal cells [107], [111], gpcr signaling [112]. Another receptor that is highly expressed in MCL compared to other NHLs is the S1P receptor S1PR1. S1PR1 was detected via immunohistochemistry in 19/19 lymph node, 10/10 gastrointestinal tract and 9/9 bone marrow MCL cases but less frequently in other NHLs [117]. S1PR1 protein was also more highly expressed than S1PR2 and S1PR3 in MCL [118]. Finally, exome sequencing of patient samples identified mutations in the S1PR1 gene in 2/11 (18%) cases [119] as well as in the Mas-related GPCR MRGPRF in 3/56 (5%) cases [120]. The estrogen receptor GPER1 is enriched in MCL as it was detected via IHC in 94/157 (60%) MCL patient samples compared to 1/20 (5%) FL cases and 6/20 (30%) diffuse large B cell lymphoma (DLBCL) cases. Knockdown of GPER1 in MCL cell lines resulted in stabilization of microtubules, inhibition of proliferation, and activation of apoptotic pathways and combining GPER1 inhibitors with additional chemotherapeutics had a synergistic effect [121].