Other GPCRs that have been described in B ALL

Other GPCRs that have been described in B-ALL include oncogenic roles for the prostaglandin receptor PTGER2 [34], [35], [36], [37] and orphan receptor GPR34 [38], increased protein expression of the thrombin receptor F2R (also known as PAR1) at significantly higher levels than lymphocytes from healthy donors [39] and decreased expression of S1PR1 and S1PR2 transcripts [40] and the tachykinin receptor TACR1 in tumor compared to normal B lymphocytes [41]. A summary of all GPCRs reported in B-ALL is shown in Table 2.
Chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a heterogeneous disease that arises from CD5+ B cells. CLL is the most frequently occurring leukemia in Western countries and has an extremely variable prognosis that can range from stable, indolent disease not requiring intervention to aggressive malignancy [42]. CLL is often characterized by immunoglobulin heavy-chain variable region gene (IGHV) mutation status. Unmutated IGHV CLL originates from pre-germinal center 69 7 sale and is defined as having less than a 2% difference between leukemic clone and germline DNA sequence in the IGHV region. Mutated IGHV arises from post-germinal center cells and contains a 2% or greater difference between leukemic clone and germline IGHV sequence and has a significantly better prognosis than unmutated IGHV [43]. CLL that localizes to lymph nodes is also known as small lymphocytic lymphoma (SLL) and represents a subset of CLL. A variety of receptors spanning multiple GPCR families have been studied in CLL and recent attempts to target members of the lipid receptors in vitro and in vivo have shown a range of success. The sphingosine-1-phosphate (S1P) receptors S1PR1 and S1PR2 transcripts were found to be downregulated in CLL compared to control B cells [40], with S1PR1 expression particularly reduced in unmutated IGHV CLL patients and S1PR2 impaired in both mutated and unmutated CLL [43]. This downregulation is thought to be due to cell interaction with the tumor microenvironment to regulate egress of malignant cells from the lymphoid tissues to peripheral blood [44]. Treatment with Syk, Btk, and B cell receptor (BCR) inhibitors has been effective at increasing S1PR1 protein expression to induce CLL cell mobilization into the blood so that cells are more sensitive to cytotoxic drugs [44], [45], [46]. Contrary to the downregulation of S1PR family GPCRs, CLL cells have increased mRNA expression of the lysophosphatidic acid (LPA) family receptors LPAR1, LPAR3 and LPAR4 compared to normal B cells [47]. Increased LPAR1 mRNA has been shown to be associated with more aggressive disease [47] and LPA signaling was found to act as a survival factor by protecting primary CLL cells from spontaneous and chemotherapy-induced apoptosis [48]. Further study revealed that treatment of B cell lines with LPA induced vascular endothelial growth factor (VEGF) expression via activation of c-Jun N-terminal kinases (JNK) and nuclear factor-kappa B (NF-κB) and protected cells against apoptosis [47], [49].