A small molecule BCL6 inhibitor as chemosensitizers in acute myeloid leukemia

BCL6 is a transcriptional repressor that regulates multiple genes involved in immune cell differentiation, DNA damage repair, cell cycle, and apoptosis, and is a carcinogenic factor in acute myeloid leukemia (AML). AML is one of the four major types of leukemia with the 5-year survival rate of patients is less than 20% and chemotherapy resistance remains the major obstacle to the treatment failure of AML. We identified WK499, a small molecule compound that can bind to BCL6BTB structure. Treatment with WK499 hinders the interactions between BCL6 with its corepressor proteins, resulting in a remarkable change of BCL6 downstream genes and anti proliferative effects in AML cells, and inducing cell cycle arrest and apoptosis. We verified that AraC and DOXo could induce BCL6 expression in AML cells, and found that WK499 had a synergistic effect when combined with chemotherapeutic drugs. We further proved that WK499 and AraC could achieve a better result of inhibiting the growth of AML in vivo. These findings indicate that WK499, a small molecule inhibitor of BCL6, not only inhibits the proliferation of AML, but also provides an effective therapeutic strategy for increasing AML sensitivity to chemotherapy.