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. 2024 Aug 22;10(16):e36640.
doi: 10.1016/j.heliyon.2024.e36640. eCollection 2024 Aug 30.

Pharmaceutical inhibition of BCL6 ameliorates resistance to imatinib in chronic myeloid leukemia

Yingying Xiao  1 , Fang Deng  2 , Yun Luo  1 , Teng Wang  1
Affiliations

Pharmaceutical inhibition of BCL6 ameliorates resistance to imatinib in chronic myeloid leukemia

Yingying Xiao et al. Heliyon. .

Abstract

The tyrosine kinase inhibitors (TKIs) have improved overall survival of CML (chronic myeloid leukemia) patients and allow them to experience normal life expectancy. However, relapse and drug resistance remain the main challenges in the clinical treatment of CML. The B-cell lymphoma 6 (BCL6) is essential to regulation of multiple function such as immune response and lymphomagenesis in lymph node germinal cells. Recent studies have shown that BCL6 is required for the maintenance of leukemia stem cells in CML, but the expression of Bcl-6 in response to Imatinib and the underlying mechanism are still unclear. Here, we found that BCL6 is expressed at high levels in primary CML bone marrow samples and CML TKI-resistance cell lines. CML cells with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, BI-3812. Treatment of CML cells with BCL6 inhibitor and TKIs suggested enhanced anti-leukemia activity. In summary, our findings suggest BCL6 as a therapeutic target for the treatment of CML.

Keywords: BI-3812; Bcl6 inhibitor; Chronic myeloid leukemia; Imatinib; Resistance.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The gate was set based on the surface markers of granulocytes and stem cells, and the expression levels of Bcl6 were compared between healthy individuals and patients with initial diagnosis of chronic phase (A-C and E-G). Collected prognosis information from 48 clinical CML patients for statistical analysis of the relationship between Bcl6 expression and prognosis (D, H).
Fig. 2
Fig. 2
Flow cytometry was used to detect the expression levels of BCL6 in CML cell lines (A, B). After a 48-h treatment with imatinib, the expression levels of BCL6 and BCL2 were examined in both sensitive and resistant CML cell lines (C, D). Western blot analysis was performed to assess the expression levels of BCL6 in CML cells at different time points following treatment with IM (E, F). The full, non-adjusted images as Supplementary Fig. S2.
Fig. 3
Fig. 3
After treating CML cells with different concentrations of imatinib, the protein expression levels of molecules related to the BCL6-Arf signaling pathway were examined using Western blot analysis (A–F). The full, non-adjusted images as Supplementary Fig. S3.
Fig. 4
Fig. 4
After treating CML cells with different concentrations of BI-3812 at various time points, the cell proliferation status was assessed (A, B). Additionally, the protein expression levels of BCL6 were examined (C, D). The results of the colony formation assay after treating cells with BI-3812 for 72 h were obtained (E, F). The changes in cell apoptosis were evaluated at different time points following treatment with BI-3812 (G, H). The full, non-adjusted images as Supplementary Fig. S4.
Fig. 5
Fig. 5
After treating CML cells with 10 μM of BI-3812 for various periods, the protein expression levels of molecules related to the BCL6-Arf signaling pathway were examined (A–D). Additionally, the changes in the expression of these molecules were assessed after treating the cells with different concentrations of BI-3812 (E).The full, non-adjusted images as Supplementary Fig. S5.
Fig. 6
Fig. 6
Different concentrations of BI-3812 were applied to the cells, and cell proliferation in K562 (A) and K562R (B) cell lines was measured using the CCK-8 assay. The changes in apoptosis status were evaluated after treating the cells with different concentrations of BI-3812 in both K562 and K562R cell lines (C–L). Statistical analysis was performed to assess the apoptosis status of CML cells after treatment with BI-3812, IM, or their combination, either individually or in combination (M − N).
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