β-Catenin Expression Is Increased in Imatinib-Resistant Chronic Myelogenous Leukemia.
Xiaohui Zhang, Lynn Moscinski, William W Bulkeley, Bijal Shah, Javier Pinilla-Ibarz, Ling Zhang. University of South Florida College of Medicine, Tampa; Moffitt Cancer Center and Research Center, Tampa, FL
Background: Imatinib treatment is the standard of care for chronic myelogeneous leukemia (CML). However, resistance occurs during the treatment partially due to Abl-kinase mutations. The other underlying mechanisms remain unclear. The Wnt/β-catenin signaling pathway is recently found to be involved in regulating the survival of hematopoietic stem cells and disease progression of CML. In this study, we investigate whether β-catenin expression correlates with imatinib resistance.
Design: Data of patients with CML during 1999-2010, including clinical history, bone marrow (BM) biopsy, cytogenetics, and molecular pathology were retrieved. Immunohistochemical stains for β-catenin were carried out on BM specimens obtained at initial diagnosis of CML chronic phase and at BM biopsy when imatinib-resistance was developed. β-Catenin positivity rates were evaluated by counting 1000 BM cells.
Results: Of 208 patients with CML, 23 developed imatinib resistance in an average of 36 months (range: 7 to 84 months). Besides t(9, 22)(q34; q11.2), additional cytogenetic changes included trisomy 8 in 2 cases, ins(8;8)(q13;q13q22) in 1 case, and -Y in 1 case. Abl-kinase mutations were detected in 10 of 16 tested patients (62.5%). In immunohistochemistry, β-catenin positive cells were mainly myeloid precursors with rare megakaryocytes. β-catenin staining was minimal on the BM at diagnosis before imatinib therapy (0.92±1.7%). In comparison, when imatinib resistance was developed, β-catenin positive cells were significantly increased (8.1±6.2%) (Figure 1). Paired student t-test was performed and showed the difference is statistically significant (P=0.0028). In these cases, low blast cell counts (average 3%) were documented, and additional clonal cytogenetic status appears irrelevant.
Conclusions: β-catenin expression is increased in the bone marrow cells of imatinib-resistant CML, independent of blast count, and additional cytogenetic aberrations. Its elevated expression suggests that Wnt/β-catenin signaling pathway may play a critical role in the development of imatinib resistance.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 166, Monday Morning