PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells

YY‑20394 (linperlisib), a highly specific PI3Kδ inhibitor, has demonstrated promising efficacy in a variety of hematological malignancies in clinical trials. ABT199 (venetoclax) as a monotherapy shows limited effects in acute myeloid leukemia (AML), underscoring the need for novel combinatorial therapeutic strategies. The drug sensitivity and potential synergistic effects of YY‑20394 and ABT199 were evaluated in three AML cell lines, MV‑4‑11, U937 and THP‑1, using a Cell Counting Kit‑8 assay. Apoptosis and cell cycle distribution were assessed using dual acridine orange/ethidium bromide staining and flow cytometry. Reverse transcription‑quantitative PCR and western blot analyses were employed to quantify the levels of Bcl‑2 apoptotic family members, c‑Myc, Akt and ERK. YY‑20394 inhibited the viability of MV‑4‑11, U937 and THP‑1 cells in a concentration‑dependent manner. In U937 cells, the highest IC50 value was observed, and YY‑20394 effectively suppressed their proliferation, induced apoptosis and caused cell cycle arrest. Furthermore, the combination of YY‑20394 and ABT199 demonstrated a synergistic effect in MV‑4‑11 cells, significantly enhancing apoptosis compared with either agent alone. Compared with the negative control group, the levels of c‑Myc and Akt phosphorylation were significantly reduced in the YY‑20394 group, and their inhibitory effects were retained in the combination group. ERK phosphorylation was significantly increased in the combination group. However, alterations in the Bcl‑2 pathways did not show a pattern consistent with the observed apoptotic phenotype. In summary, YY‑20394 is effective for inhibiting proliferation of AML cells, and its combination with ABT199 has synergistic pro‑apoptotic effects in MV‑4‑11 cells, which provides new insights and potential avenues for the treatment of AML and its subtypes. Further studies are warranted to explore the therapeutic efficacy and underlying molecular mechanisms of this combination in additional AML subtypes.