Other GPCRs notable for changes in expression on CLL cells
Other GPCRs notable for changes in expression on CLL cells include upregulation of the thromboxane A2 receptor TBXA2R mRNA  and up and downregulation of mRNA and protein from the neurotensin receptors NTSR2 and NTSR1, respectively . The Eμ-TCL1 mouse model of CLL has been used to study multiple aspects of the disease including changes in gene expression during disease development. In this model, the gene expression of the Wnt/Fzd pathway GPCRs FZD6 and FZD1 both increased during leukemogenesis and knockout of FZD6 in the model resulted in a delay and decreased incidence of disease . However, differences between mouse and human FZD6 have made it challenging to understand the relation of this finding to humans . In a study of human mRNA, FZD3 was the only Fzd receptor that had significantly higher expression in mutated or unmutated CLL when compared to normal cerk . FZD3 mRNA was also found to be overexpressed in a separate cohort of early-stage CLL patients compared to normal volunteers . The expression levels of chemokine receptors in CLL and SLL are summarized in Table 1 and their role in disease has been reviewed elsewhere . Of note, CXCR3 is highly expressed in CLL and plays a role in mediating cell chemotaxis. In one study, 31/31 (100%) CLL patients had CD5+ B cells positive for CXCR3 via flow cytometry compared to 0/6 (0%) healthy subjects  while in another study CXCR3 was positively identified via IHC in 34/36 (94%) CLL/SLL patients and by flow cytometry in 12/13 (92%) cases . CXCR3 was also found to be overexpressed in low stage CLL compared to healthy B cells via gene expression profiling . With regards to the consequences of CXCR3 expression, one study with a small cohort of 21 patients found no correlation between CXCR3 flow cytometry mean fluorescence intensity (MFI) and the number of lymphocytes or clinical stage of disease  whereas a larger study of 149 CLL patients found that patients with high CXCR3 and low CXCR4 MFI had a significantly lower risk of disease progression in both IGHV mutated and unmutated CLL . CLL cells express an abundance of CXCR4 protein , , , , ,  to enable migration and infiltration of bone marrow . Increased protein levels of CXCR4 were found to be associated with survival in familial CLL  and lymphadenopathy  but it is unclear whether they do  or do not correlate with disease stage . Multiple genetic aberrations of CXCR4 in CLL have been discovered including 3/186 (2%) familial cases of CLL containing a mutation in the coding region of the gene  and a case study of a translocation resulting in a CXCR4/MAML2 (mastermind like transcriptional coactivator 2) fusion protein . As CLL cells do not express CXCR7 protein, all CXCL12-mediated responses are accomplished via CXCR4 and numerous downstream signaling molecules including activation of ZAP-70, MAPK and Akt signaling pathways , , . CXCR4 was observed to be hyperphosphorylated in CLL compared to normal lymphocytes and inhibition of PIM kinase caused dephosphorylation and internalization of CXCR4 . Numerous other therapeutics targeting CXCR4 downregulation have been investigated including suberoylanilide hydroxamic acid , AMD3100 (plerixafor) , the combination of CXCR4 antagonists and passive immunotherapy , PI3K inhibitors , small peptide inhibitors  and ibrutinib-mediated BTK inhibition , . The chemokine receptor CXCR5 plays a significant role in CLL/SLL pathogenesis. The receptor protein has been identified on greater than 90% of patient samples , , ,  and shown not to be affected by IGHV mutation status . Depending on the study, CXCR5 protein was either similarly expressed or significantly overexpressed relative to normal CD5+ B cells , ,  and more highly expressed in CLL compared to other B cell neoplasms , , , . Downregulation of CXCR4 and CXCR5 via BCR signaling was found to correlate with unfavorable disease outcome ,  and reduced CXCR5 MFI was observed in del 17p/11q CLL, which has a worse prognosis than normal CLL . Experiments in cell lines revealed that overexpression of CXCR5 along with CCR7 in CLL and B-ALL enabled resistance to apoptosis via upregulation of PEG10 and stabilization of caspase-3 and caspase-8 , . In concordance with these findings and its proposed role as on oncogene, knockout of CXCR5 in the Eμ-TCL1 CLL mouse model resulted in significantly delayed disease onset and disrupted leukemia cell migration .