C-C chemokine receptor 1 expression in human hematolymphoid neoplasia

Abstract

Chemokine receptor 1 (CCR1) is a G protein-coupled receptor that binds to members of the C-C chemokine family. Recently, CCL3 (MIP-1alpha), a high-affinity CCR1 ligand, was identified as part of a model that independently predicts survival in patients with diffuse large B-cell lymphoma (DLBCL). However, the role of chemokine signaling in the pathogenesis of human lymphomas is unclear. In normal human hematopoietic tissues, we found CCR1 expression in intraepithelial B cells of human tonsil and granulocytic/monocytic cells in the bone marrow. Immunohistochemical analysis of 944 cases of hematolymphoid neoplasia identified CCR1 expression in a subset of B- and T-cell lymphomas, plasma cell myeloma, acute myeloid leukemia, and classical Hodgkin lymphoma. CCR1 expression correlated with the non-germinal center subtype of DLBCL but did not predict overall survival in follicular lymphoma. These data suggest that CCR1 may be useful for lymphoma classification and support a role for chemokine signaling in the pathogenesis of hematolymphoid neoplasia.

Figure 1

Kaplan-Meier estimate of overall survival in patients with follicular lymphoma. A, Follicular Lymphoma International Prognostic Index scores predict overall survival. P = .027. B, Chemokine receptor 1 (CCR1) expression level is not correlated with overall survival. CCR1 levels were scored as follows: 0, negative; 1, uninterpretable; 2, 5%–20% of cells positive; and 3, >20% of cells positive. P = .60.

Image 1

Immunohistologic staining for chemokine receptor 1 (CCR1) protein in normal human hematopoietic tissues. A, CCR1 protein (red, cytoplasm and cell membrane) is predominantly localized to intraepithelial lymphocytes within the tonsillar crypts (×100). B, Double immunolabeling of tonsil sections shows colocalization of CCR1 (red) with CD20 (brown, membrane) on B lymphocytes within the tonsillar crypt epithelium (×400). C, Rare CCR1-expressing cells within the germinal center (red) show dendritic cell morphologic features and do not colocalize with CD20 (brown) (×600). D, In normal bone marrow, CCR1 is expressed by cells of the granulocyte-monocyte lineage but not in cells of the erythroid lineage (×400). E, In the spleen, CCR1 protein expression is found largely within granulocytes in the red pulp. No significant CCR1 staining is present within the germinal centers of the white pulp (×200). F, In the thymus, CCR1 highlights medullary dendritic cells and the Hassall corpuscles without significant staining of cortical thymocytes (×100). Rare cases show CCR1 expression by cortical epithelial cells (inset, ×400).

Image 1

Immunohistologic staining for chemokine receptor 1 (CCR1) protein in normal human hematopoietic tissues. A, CCR1 protein (red, cytoplasm and cell membrane) is predominantly localized to intraepithelial lymphocytes within the tonsillar crypts (×100). B, Double immunolabeling of tonsil sections shows colocalization of CCR1 (red) with CD20 (brown, membrane) on B lymphocytes within the tonsillar crypt epithelium (×400). C, Rare CCR1-expressing cells within the germinal center (red) show dendritic cell morphologic features and do not colocalize with CD20 (brown) (×600). D, In normal bone marrow, CCR1 is expressed by cells of the granulocyte-monocyte lineage but not in cells of the erythroid lineage (×400). E, In the spleen, CCR1 protein expression is found largely within granulocytes in the red pulp. No significant CCR1 staining is present within the germinal centers of the white pulp (×200). F, In the thymus, CCR1 highlights medullary dendritic cells and the Hassall corpuscles without significant staining of cortical thymocytes (×100). Rare cases show CCR1 expression by cortical epithelial cells (inset, ×400).

Image 2

Immunohistologic staining for chemokine receptor 1 (CCR1) protein expression in human hematolymphoid neoplasia. Representative examples of CCR1 immunostaining in human lymphomas and leukemia are shown. CCR1 is expressed in cases of diffuse large B-cell lymphoma (A, ×400) and follicular lymphoma (C, ×40), with negative examples provided for comparison (B, ×400; D, ×40). In follicular lymphoma, CCR1 expression is present on the neoplastic cells (C, inset, ×400). While CCR1 expression was present in cases of classical Hodgkin lymphoma (G, ×400), expression was largely absent in cases of extranodal marginal zone lymphoma (F, ×400), small lymphocytic lymphoma/chronic lymphocytic leukemia (E, ×400), and nodular lymphocyte predominant Hodgkin lymphoma (H, ×400). CCR1 was expressed by T-cell lymphomas, including peripheral T-cell lymphoma, not otherwise specified (I, ×400) and anaplastic large cell lymphoma (J, ×400). CCR1 expression was present in a majority of cases of multiple myeloma (K, ×400) and acute myeloid leukemia (L, ×400).

Image 2

Immunohistologic staining for chemokine receptor 1 (CCR1) protein expression in human hematolymphoid neoplasia. Representative examples of CCR1 immunostaining in human lymphomas and leukemia are shown. CCR1 is expressed in cases of diffuse large B-cell lymphoma (A, ×400) and follicular lymphoma (C, ×40), with negative examples provided for comparison (B, ×400; D, ×40). In follicular lymphoma, CCR1 expression is present on the neoplastic cells (C, inset, ×400). While CCR1 expression was present in cases of classical Hodgkin lymphoma (G, ×400), expression was largely absent in cases of extranodal marginal zone lymphoma (F, ×400), small lymphocytic lymphoma/chronic lymphocytic leukemia (E, ×400), and nodular lymphocyte predominant Hodgkin lymphoma (H, ×400). CCR1 was expressed by T-cell lymphomas, including peripheral T-cell lymphoma, not otherwise specified (I, ×400) and anaplastic large cell lymphoma (J, ×400). CCR1 expression was present in a majority of cases of multiple myeloma (K, ×400) and acute myeloid leukemia (L, ×400).

Image 3

Hierarchical cluster analysis of immunohistologic results for diffuse large B-cell lymphoma (DLBCL). The expression patterns of LMO2, human germinal center–associated lymphoma (HGAL), CD10, BCL6, BCL2, MUM1, and chemokine receptor 1 (CCR1) in 143 cases of DLBCL are shown. Positive staining is represented in red, negative staining in green, and uninformative data (loss of core tissue) in white. CCR1 protein expression clusters on the dendrogram branch, which includes the non–germinal center (GC) markers BCL2 and MUM1, and away from the GC-associated markers LMO2, BCL6, CD10, and HGAL.