The immunohistochemical staining pattern of Gab2 correlates with distinct stages of chronic myeloid leukemia

Abstract

Grb2-associated binder 2 protein (Gab2) is a member of scaffold proteins, playing crucial roles in (receptor-) tyrosine kinase and cytokine signaling. Chronic myeloid leukemia cells with t(9;22)(q34;q11) express the Bcr/Abl fusion protein, which interacts with Grb2 and Gab2 signaling, thereby triggering hematopoietic cell proliferation. The aim of this study was to examine in detail the total and subcellular Gab2 protein expression in myeloid cells in bone marrow biopsies of patients with chronic myeloid leukemia in different disease stages. The study included 50 fixed bone marrow biopsies of controls (unaffected hematopoiesis, n = 11) and Bcr/Abl-positive chronic myeloid leukemia cases (n = 39) of different stages (chronic phase, n = 13; accelerated phase, n = 4; blast crisis, n = 11; complete remission, n = 11). Immunohistochemistry and quantitative evaluation of Gab2 staining in 600 myeloid cells/bone marrow biopsy were performed before statistical analyses. Immunohistochemistry revealed Gab2 expression in hematopoietic cells. Gab2-positive myeloid cells occurred significantly more frequent in chronic myeloid leukemia cases than in controls (P < .001) and appeared to markedly increase from chronic phase to accelerated phase to blast crisis. Importantly, within the distinct stages of chronic myeloid leukemia, a significant switch of Gab2-positive myeloid cells with cytoplasmic or nuclear/perinuclear Gab2 staining occurred: Nuclear/perinuclear Gab2-positive myeloid cells significantly increased from chronic phase to accelerated phase (P = .001) and from chronic phase to blast crisis (P < .001). Still, an overlap and, hence, a wider range of Gab2 staining patterns were seen between and within chronic myeloid leukemia stages, most likely reflecting a high plasticity of Grb2-associated binder 2 functions in the progression of chronic myeloid leukemia. In summary, the present study, for the first time, analyzed Grb2-associated binder 2 protein expression in bone marrow biopsies of patients with chronic myeloid leukemia in detail, demonstrating a novel and distinct Grb2-associated binder 2 staining pattern in normal and chronic myeloid leukemia bone marrow biopsies as well as in distinct chronic myeloid leukemia stages. Grb2-associated binder 2 immunohistochemistry may provide a valuable supplementary tool to routine histopathology and standard immunohistochemistry for classification and staging of (borderline) chronic myeloid leukemia bone marrow biopsies and hence improved therapeutic disease management.