A total of 133 patients with acute myeloid leukemia (AML) were enrolled in the current study and were subdivided into 4 groups: 34 harboring DNA methyltransferase 3 α (DNMT3A) + fms related tyrosine kinase 3‑internal tandem duplication (FLT3‑ITD) mutations, 37 harboring only FLT3‑ITD mutation, 32 harboring only DNMT3A mutation and 30 harboring no mutations in DNMT3A and FLT3‑ITD (control). Patients in all groups were administered daunorubicin and cytarabine chemotherapy regimens. The rates of complete remission (CR), 1‑year relapse (RR) and 3‑year overall survival (OS) were compared. Patients in the DNMT3A + FLT3‑ITD mutation group exhibited higher proportions of peripheral white blood cells (WBCs) and myeloid progenitor cells compared with those in DNMT3A mutation only, FLT3‑ITD mutation only and control groups (P<0.05). The rates of CD15+ and HLA‑DR+ in the DNMT3A + FLT3‑ITD mutation and DNMT3A mutation only groups were significantly higher than those in the FLT3‑ITD mutation only and control groups (P<0.05); in addition, the rate of CD38+ in the DNMT3A + FLT3‑ITD mutation and FLT3‑ITD mutation only groups was significantly higher compared with that in the DNMT3A mutation only and control groups (P<0.05). The overall chemotherapy effectiveness rate, CR, 1‑year RR and the 3‑year OS rates of patients in the DNMT3A + FLT3‑ITD mutation group were significantly worse compared with FLT3‑ITD mutation only, DNMT3A mutation only and control groups (P<0.05). The results of this study indicated that increased mutation rates in DNMT3Α and FLT3‑ITD may be associated with increased WBC and myeloid progenitor cell counts, an inferior chemotherapy efficacy and prognosis, a lower CR rate, and higher 1‑year RR and mortality rate.
The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely5-3, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that5-3potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of5-3depends highly on FLT3-ITD expression. Mechanically,5-3significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound5-3is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that5-3might be a drug candidate for the treatment of FLT3-ITD-positive AML.
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