Characterization of the Novel Germinal Center Marker KLHL6 in Human Lymphomas
Christian A Kunder, Shuchun Zhao, Ezequiel G Martinez, Giovanna Roncador, Arasha A Alizadeh, Izidore S Lossos, Yasodha Natkunam. Stanford University, Stanford, CA; CNIO National Cancer Insitute, Madrid, Spain; University of Miami, Miami, FL
Background: KLHL6 is a recently described BTB-Kelch protein, which is selectively expressed throughout B cell ontology and is strongly upregulated in germinal center B cells. BTB-kelch proteins contain BTB and Kelch domains, both of which are evolutionarily conserved motifs with numerous functions. Members of this protein family are involved in a variety of diverse cellular processes, including cytoskeletal rearrangement and cell motility, as well as regulation of gene expression and protein turnover, among others. KLHL6 knockout mice demonstrated smaller germinal centers, reduced B cell expansion and reduced memory antibody responses. Further, B lymphocytes from KLHL6 knockout mice were less sensitive to B cell receptor signaling. Mutations in KLHL6 have recently been identified in human lymphomas, but little information is available overall concerning its expression and function in human lymphocytes and lymphoid neoplasms.
Design: Using immunohistochemistry with an anti-KLHL6 monoclonal antibody, we have characterized the expression of this protein in normal hematopoietic tissues as well as in 320 human neoplasms.
Results: Consistent with its enhanced expression in germinal center B cells, KLHL6 was positive mainly in B cell neoplasms of germinal center derivation, including 81.6% of follicular lymphomas and 54.7% of diffuse large B cell lymphomas. B cell lymphomas of non-germinal center derivation were generally negative. In normal hematopoietic tissues, KLHL6 labeled germinal center B cells. Interestingly, rare cells associated with Hassall's corpuscles were also positive.
|Neoplasm||No. of cases||No. of positive cases||Percent positive|
|Diffuse large B cell lymphoma||64||35||54.7%|
|Mantle cell lymphoma||11||0||0%|
|Chronic lymphocytic leukmia/small lymphocytic lymphoma||33||0||0%|
|Extranodal marginal zone lymphoma||11||0||0%|
|Nodal marginal zone lymphoma||5||1||20%|
|Splenic marginal zone lymphoma||4||0||0%|
|Post-transplant lymphoproliferative disease||2||2||100%|
|Nodular lymphocyte predominant Hodgkin lymphoma||2||2||100%|
|B lymphoblastic leukemia||4||0||0%|
|T lymphoblastic leukemia||9||0||0%|
|T cell lymphomas||30||1||3.3%|
|Acute myeloid leukemia||11||0||0%|
|NK cell lymphoma||3||0||0%|