Characterization of c-Maf transcription factor in normal and neoplastic hematolymphoid tissue and its relevance in plasma cell neoplasia

Abstract

c-Maf, a leucine zipper-containing transcription factor, is involved in the t(14;16)(q32;q23) translocation found in 5% of myelomas. A causal role for c-Maf in myeloma pathogenesis has been proposed, but data on c-Maf protein expression are lacking. We therefore studied the expression of c-Maf protein by immunohistochemical analysis in myelomas and in a wide variety of hematopoietic tissue. c-Maf protein was detected in a small minority (4.3%) of myelomas, including a t(14;16)(q32;q22-23)/IgH-Maf+ case, suggesting that c-Maf protein is not expressed in the absence of c-Maf rearrangement. In contrast, c-Maf was strongly expressed in hairy cell leukemia (4/4) and in a significant proportion of T-cell (24/42 [57%]) and NK/T-cell (49/97 [51%]) lymphomas, which is in keeping with prior gene expression profiling and transgenic mouse studies. Up-regulation of c-Maf protein occurs in a small subset of myelomas, in hairy cell leukemia, and in T- and NK-cell neoplasms. Its detection may be of particular value in the differential diagnosis of small cell lymphomas.

Image 1

Immunohistochemical staining for c-Maf in normal hematopoietic tissue. A and B, Low- and high-magnification images of normal tonsil sections with c-Maf–specific staining within the nuclei of many cells in germinal centers and interfollicular areas; however, plasma cells were negative (A, ×10; B, ×40). C and D, In the thymus (C, ×10) and bone marrow (D, ×60), c-Maf staining was largely absent and was restricted to occasional histiocytes, plasma cells, and lymphocytes. E and F, Double immunohistologic labeling of c-Maf and plasma cell–associated markers CD38 (E, ×10) and CD138 (F, ×10) shows that the vast majority of c-Maf+ cells did not coexpress the other plasma cell markers tested. G and H, c-Maf was also expressed in scattered cells within the interfollicular T zones, and double labeling showed that these were commonly CD3+ (G, ×10) and germinal center T cell–associated marker SAP-positive (H, ×10) T cells (high-magnification insets, ×100-×300).

Image 1

Immunohistochemical staining for c-Maf in normal hematopoietic tissue. A and B, Low- and high-magnification images of normal tonsil sections with c-Maf–specific staining within the nuclei of many cells in germinal centers and interfollicular areas; however, plasma cells were negative (A, ×10; B, ×40). C and D, In the thymus (C, ×10) and bone marrow (D, ×60), c-Maf staining was largely absent and was restricted to occasional histiocytes, plasma cells, and lymphocytes. E and F, Double immunohistologic labeling of c-Maf and plasma cell–associated markers CD38 (E, ×10) and CD138 (F, ×10) shows that the vast majority of c-Maf+ cells did not coexpress the other plasma cell markers tested. G and H, c-Maf was also expressed in scattered cells within the interfollicular T zones, and double labeling showed that these were commonly CD3+ (G, ×10) and germinal center T cell–associated marker SAP-positive (H, ×10) T cells (high-magnification insets, ×100-×300).

Image 2

Immunohistologic staining for c-Maf in hematolymphoid neoplasia. Representative examples of c-Maf immunostaining in hairy cell leukemia (A, ×60), myeloma (B, ×40), splenic marginal zone lymphoma (C, ×20), T-lymphoblastic lymphoma (D, ×40), NK-cell lymphoma (E, ×40), and peripheral T-cell lymphoma (F, ×40) are shown. All 4 cases of hairy cell leukemia showed strong nuclear reactivity for c-Maf, whereas none of the splenic marginal zone lymphomas were positive. A significant proportion of precursor and mature T-cell and NK-cell lymphomas showed c-Maf protein expression (high-magnification insets, ×300).

Image 2

Immunohistologic staining for c-Maf in hematolymphoid neoplasia. Representative examples of c-Maf immunostaining in hairy cell leukemia (A, ×60), myeloma (B, ×40), splenic marginal zone lymphoma (C, ×20), T-lymphoblastic lymphoma (D, ×40), NK-cell lymphoma (E, ×40), and peripheral T-cell lymphoma (F, ×40) are shown. All 4 cases of hairy cell leukemia showed strong nuclear reactivity for c-Maf, whereas none of the splenic marginal zone lymphomas were positive. A significant proportion of precursor and mature T-cell and NK-cell lymphomas showed c-Maf protein expression (high-magnification insets, ×300).

Image 3

Hierarchical cluster analysis of immunohistologic data. The expression patterns of 7 proteins, c-Maf, ICSBP, LIME, SIT, BLIMP-1, CD138, and MUM1/IRF4 (MUM1), in 143 cases of myeloma are shown. Strong positive staining (score 3) is indicated in bright red, weak positive staining (score 2) in dark red, lack of staining (score 0) in green, and uninformative data (score 1) in white. c-Maf protein expression is most closely clustered with that of ICSBP (not expressed or expressed in a minority of cases), followed by LIME and SIT (expressed in approximately 40%-60% of cases). c-Maf expression was most unlike that of IRF4/MUM1, CD138, and BLIMP-1 (clustered on a separate branch on the dendrogram), which were expressed in more than 80% of the myelomas studied.