Abstract
Acute myeloid leukemia (AML) is a heterogeneous myeloid neoplasm with poor clinical outcome, despite the great progress in treatment in recent years. The selective Bcl-2 inhibitor venetoclax (ABT-199) in combination therapy has been approved for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy, but resistance can be acquired through the upregulation of alternative antiapoptotic proteins. Here, we reported that a newly emerged histone deacetylase inhibitor, chidamide (CS055), at low-cytotoxicity dose enhanced the anti-AML activity of ABT-199, while sparing normal hematopoietic progenitor cells. Moreover, we also found that chidamide showed a superior resensitization effect than romidepsin in potentiation of ABT-199 lethality. Inhibition of multiple HDACs rather than some single component might be required. The combination therapy was also effective in primary AML blasts and stem/progenitor cells regardless of disease status and genetic aberrance, as well as in a patient-derived xenograft model carrying FLT3-ITD mutation. Mechanistically, CS055 promoted leukemia suppression through DNA double-strand break and altered unbalance of anti- and pro-apoptotic proteins (e.g., Mcl-1 and Bcl-xL downregulation, and Bim upregulation). Taken together, these results show the high therapeutic potential of ABT-199/CS055 combination in AML treatment, representing a potent and alternative salvage therapy for the treatment of relapsed and refractory patients with AML.
Highlights
Acute myeloid leukemia (AML) is a highly aggressive hematopoietic neoplasm characterized by the clonal expansion of myeloid blasts and impaired hematopoiesis[1]
We first examined whether the selective Histone deacetylase inhibitors (HDACi) CS055 potentiated the cytotoxicity of ABT-199 in various human AML cell lines after Annexin V/PI staining
Bcl-2 inhibitors directly targeting the regulatory machinery of apoptosis[30], as well as epigenetic therapy[36]
Summary
Acute myeloid leukemia (AML) is a highly aggressive hematopoietic neoplasm characterized by the clonal expansion of myeloid blasts and impaired hematopoiesis[1]. Evasion of apoptosis and enhanced tumor cell survival via dysregulation of Bcl-2 family members is one important therapeutic resistance mechanism[3,4,5]. ABT-199 (venetoclax), selectively targeting Bcl-26 but not Bcl-xL to avoid thrombocytopenia[7,8,9], is highly effective against. Drug Administration (FDA) has approved venetoclax plus rituximab for the treatment of patients with relapsed/. Refractory chronic lymphocytic leukemia carrying 17p deletion[13,14], and venetoclax in combination with hypomethylating agents (azacitidine and decitabine) or cytarabine for the treatment of newly diagnosed AML patients ineligible for intensive chemotherapy[15,16]. Resistance to ABT-199 can be acquired from upregulation of alternative antiapoptotic proteins, including the crucial pro-survival protein Mcl-117–20. Mcl-1 overexpression has been associated with high tumor grade and poor survival in cancer[21,22]
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