br Conflict of interest br Acknowledgments and

Conflict of interest
Acknowledgments and funding We thank Jaakko Matomäki, MSc, for the statistical analysis of the data. The study was supported by the Medical Research Council of the Academy of Finland, Decisions no. 250124 and 250114 (Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-17), Sigrid Jusélius Foundation, Juvenile Diabetes Research Foundation,Orion Research Foundation, The Finnish Medical Foundation and Emil Aaltonen Foundation.
Introduction GPCRs are seven-transmembrane domain cell surface-spanning receptors that regulate and transmit extracellular signals to induce numerous intracellular signaling pathways. There are hundreds of known GPCRs, each of which binds a specific ligand or set of ligands, which then induce conformational changes that lead to downstream signaling events. The cell surface ligand-binding capabilities of GPCRs make them highly desirable as drug targets for oncogenic cells. A complete and thorough understanding of GPCR expression in normal and malignant cells, coupled with a detailed knowledge of the molecules that bind to each GPCR and the downstream signaling pathways they activate, will reveal numerous opportunities for targeted therapeutics to improve disease outcome. A summary of what is known regarding GPCR expression and mutation in B cell lymphomas is reviewed here and outlined in Fig. 1.
B-cell acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a neoplasm of the lymphoid precursor Carbamazepine synthesis and is characterized as either B cell ALL (B-ALL) or T cell ALL (T-ALL) based on the cell of origin. B-ALL is the most common childhood malignancy and occurs less frequently in adults [1]. B-ALL cases are often subgrouped based on cell of origin, patient age, or the presence of a chromosomal aberration. Multiple chemokine receptors are expressed in B-ALL and these findings are summarized in Table 1. Chemokine receptor expression frequently varies between lineage-derived subgroups of B-ALL and this can provide insight into the underlying function of GPCRs in B-cell development and lymphomagenesis. For example, CXCR1 surface protein was not found in pro-B or pre-B ALL but was present in 5/17 (29%) cases of early pre-B and 3/5 (60%) cases of B-ALL [2]. Meanwhile, flow cytometry of CXCR2 and CXCR3 found these receptors to be expressed in all early pre-B, pre-B and B-ALL samples tested along with more than half of pro-B samples [2], [3]. However, another study that used immunohistochemistry (IHC) instead of flow cytometry to detect surface protein only found CXCR3 in 3/9 (33%) lymphoblastic leukemia/lymphoma patients [4]. CXCR4 is the most frequently studied chemokine receptor in lymphoma and its role in signaling in B-ALL has been extensively reviewed [5]. CXCR4 is normally expressed on pre-B and mature B cells and is essential for migration in lymphoma [4]. Elevated mRNA or protein expression of CXCR4 in B-ALL has been correlated with unfavorable clinical outcome [6], extramedullary organ invasiveness [7], [8], and time point and site of relapse [9]. CXCR4 has been identified in the majority of pro-B, pre-B and B-ALL cases and in some early pre-B cases [2], [3], [8], [10]. The estrogen receptor GPER1 (also known as GPR30) is also believed to regulate CXCR4 signaling in pre-B cell ALL [11]. CXCR5 is known to play a role in signaling and cell migration in lymphoma, however there are conflicting reports regarding its cell surface expression in B-ALL. Two flow cytometry studies did not identify any precursor-B, pro-B or pre-B patients with CXCR5 expressed [3], [10] while a third study found CXCR5+ cases in 3/9 (33%) pro-B, 5/17 (29%) early pre-B, 4/12 (33%) pre-B and 5/5 (100%) B-ALL cases [2]. A fourth report identified CXCR5 expression only on CD23+ CD5+ B-ALL cells [12], while a final study found the receptor to be expressed in all B-ALL cases [4]. Other chemokine receptors that have been detected by flow cytometry in B-ALL include CCR3 and CCR4 [2], [12] as well as CXCR7 (also known as ACKR3), which is strongly upregulated in the bone marrow in B-ALL compared to normal tissue and plays a role in controlling CXCR4-mediated migration [13]. CCR7 cell surface expression has been found to vary between studies [2], [3], [12] while CCR1, CCR2, CCR5 and CCR6 were extremely rarely or never expressed [2], [3], [10], [14].