Bone Marrow Beta-Catenin Expression In Chronic Myelogenous Leukemia Patients Treated With Imatinib

Imatinib is the standard of care for treating chronic myelogeneous leukemia (CML). However, it is rarely curative and patients often show resistance to the drug. ABL-kinase domain mutations are one mechanism of resistance in CML. Regulation of hematopoietic stem cell survival, as well as disease progression in CML has been linked to the Wnt/beta-catenin pathway. Our study investigated the expression of beta-catenin in the bone marrow (BM) of CML patients treated with imatinib as well as its possible application as a prognostic marker for response to therapy.

Data from patients with chronic phase (CP) CML treated at Moffitt Cancer Center between 1999 and 2011, including clinical history, BM biopsies, cytogenetics, and molecular pathology was reviewed. Immunohistochemical stains for beta-catenin were carried out on BM specimens obtained at diagnosis, and after imatinib therapy. Imatinib resistant and imatinib responsive patients were included. Beta-catenin positive rates were calculated using Imagej application by counting the ratio of positive cells and hematoxylin counter-stained nuclei in multiple fields. A Student’s t-test was used to analyze differences between beta-catenin levels in different patient groups.

Bone marrow samples from 39 patients with CP-CML were analyzed. Among these, 15 developed resistance to imatinib, 10 achieved a complete cytogenetic (CCyR) or major molecular response (MMR) with imatinib, and 14 were lost to follow-up. An additional 41 bone marrows from patients with imatinib resistance were analyzed (bone marrows from diagnosis were not available in these 41 patients). By immunohistochemistry, beta-catenin was expressed mainly in myeloid precursors. Beta-catenin positive rates were low in the BM at diagnosis (3±2.8%, n=39). In patients with CCyR or MMR after imatinib, the beta-catenin positive rates increased from 1.6±1.7% to 5.3±3.3% (n=10, p=0.0007, paired t-test), whereas in patients with imatinib resistance beta-catenin positive rates increased from 3.6±3.8% to 8.9±6.0% after therapy (n=15, p=0.002, paired t-test). Beta-catenin expression in the BM at diagnosis was higher in resistant patients than in patients who achieved CCyR or MMR (1.6±1.7% vs. 3.6±3.8%, p=0.06 paired t-test). Similar differences between the two groups were seen after imatinib therapy (5.3±3.3% vs. 8.9±6.0%, p=0.06, paired t-test). The overall beta-catenin positive rates in resistant bone marrows were 7.3±6.1% (n=55) post imatinib therapy, compared to 3±2.8% (n=39) at diagnosis (p=0.00001, paired t-test).

Beta-catenin expression is increased in the BM in CML patients after imatinib therapy, with greater expression noted in patients who are resistant to imatinib. In cells carrying the BCR-ABL fusion gene, the Wnt/beta-catenin signaling pathway may play a role in resistance or disease relapse. However, in patients with adequate responses to therapy, where there is a significant reduction of the BCR-ABL fusion product, elevated beta-catenin may be associated with cell regeneration. Further study is necessary to clarify the underlying mechanism.

No relevant conflicts of interest to declare.