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  • br Lymphoplasmacytic lymphoma Waldenstrom macroglobulinemia


    Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia Lymphoplasmacytic lymphoma (LPL) and its subgroup Waldenstrom macroglobulinemia (WM) are rare and indolent lymphomas that arise from fully differentiated B cells. The only family of GPCRs that has been well studied in LPL/WM is the chemokine receptor family. Flow cytometry of WM cell lines and patient samples found 13 CXC and CC chemokine receptors were expressed to some degree [4], [14], [193] and CXCR4, in particular, was highly expressed and found to be necessary for WM migration to bone marrow [193]. CXCR4 was shown to interact with integrin α4β1 (also known as Very Late Antigen-4; VLA-4) to regulate homing and adhesion, and treatment of WM cell lines with a CXCR4 antagonist inhibited migration and signaling [193], [194]. Driver mutations in CXCR4 are an important determinant of clinical phenotype and survival in WM/LPL [195] and the role of CXCR4 in homing, migration and dissemination of WM/LPL has been well reviewed [196]. Mutations in CXCR4 were detected in 17/47 (36%) LPL cases and mutation correlated with increased bone marrow infiltration and lower leucocyte, hemoglobin and platelet counts [197]. CXCR4 mutations were also identified in 24–27% of WM patients and the mutations were heterozygous and located in the carboxy-terminal tail [198], [199], [200]. The CXCR4 C1013G mutation was detected in 37/131 (28%) cases of LPL and a novel anti-CXCR4 antibody was shown to affect survival and apoptosis signaling in WM FDA-approved Drug Library [201]. Separating LPL/WM into subgroups revealed CXCR4WHIM mutations in 2/12 (17%) Immunoglobulin M monoclonal gammopathy of undetermined significance (IgM MGUS), 0/7 (0%) Non-IgM MGUS, 44/102 (43%) untreated WM and 21/62 (34%) treated WM [192]. CXCR4 cell surface expression was increased in CXCR4-mutated cases of WM compared to CXCR4-wild type [198] but overall CXCR4 was found to be lower in WM than other NHLs [202]. Nearly all cases that have CXCR4 mutations also have MYD88 mutations [197], [200], however a small study found that only about 29% of patients with MYD88 mutations in WM also have a CXCR4 mutation [203]. Frameshift mutations in CXCR4 have also been identified and shown to result in receptor internalization in response to CXCL12 [204].
    Hairy cell leukemia Hairy cell leukemia (HCL) is a rare disease that accounts for approximately 2% of leukemias and is typically defined by cells that contain the BRAF kinase p.V600E mutation [205]. Gene expression profiling of HCL has suggested that these tumors arise from a memory B cell of origin and that transformation to lymphoma involves changes in expression of chemokine and adhesion receptors [206]. Similar to LPL/WM, studies of GPCRs in HCL mainly concern chemokine receptors and these findings are summarized in Table 1. At least two independent reports have concluded that CX3CR1, CXCR3. CXCR4, CXCR5, CCR5 and CCR6 have been identified in patient cases [3], [4], [10], [72], [103]. Meanwhile, cell surface expression of CCR7, CXCR4 and CXCR5 was found to be significantly lower in HCL compared to normal B cells or B cell neoplasms with nodular dissemination [3], [71], [206].
    Funding sources This research was supported by the Intramural Research Programs of the National Institutes of Health (Z01DK056015 and Z01DK056017), National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health.
    The dental pulp, which originates from the dental papilla, is an unmineralized oral tissue composed of soft connective tissue and vascular, lymphatic, and nerve components that occupy the central pulp cavity of the dental apparatus. In immature teeth, the dental pulp is composed of coronal pulp (CP) and apical pulp (AP). The AP is located at the apex of developing human permanent teeth, and smooth-surfaced soft tissue was easily detached from the apex to expose dental pulp tissue in the canal space. The AP originates from the dental papilla of the dental organ, which is the early tooth bud state, and there is an apical cell–rich zone lying between the CP and the apical papilla. The apical papilla appears to contain fewer blood vessels and less extracellular matrix relative to the CP and the apical cell–rich zone .