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Article Open Access

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

  • Authors:
    • Yinghua Geng
    • Lili Zhou
    • Yan Lou
    • Jiaqi Chen
    • Qi Liu
    • Ji Shen
    • Yanli Yang
    • Wenjuan Wu
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233000, P.R. China, Department of Biochemistry and Molecular Biology, Bengbu Medical University, Bengbu, Anhui 233030, P.R. China
    Copyright: © Geng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 148
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    Published online on: June 17, 2026
       https://doi.org/10.3892/or.2026.9153
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Abstract

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.
View Figures

Figure 1

Three acute myeloid leukemia lines
exhibit different sensitivities to YY-20394. The dose-response
curves indicate the percentage growth inhibition of each cell line
in response to increasing concentrations of YY-20394 for 24 or 48
h, as measured using Cell Counting Kit-8 assays. (A) THP-1 cells
were treated with YY-20394 (500–20,000 nM). (B) U937 cells treated
with YY-20394 (1,000-10,0000 nM). (C) MV-4-11 cells were treated
with YY-20394 (10–5,000 nM). Data are presented as mean ± SD from
three independent experiments. IC50, half-maximal
inhibitory concentration.

Figure 2

YY-20394 could influence the
apoptosis and cell cycle in U937 cells. (A) U937 cells were treated
with 5 and 10 µM of YY-20394 for 48 h. Early and late apoptotic
cells were stained using the acridine orange/ethidium bromide dual
staining method, and apoptosis was assessed based on the color and
morphology of the cells. Magnification, ×100; scale bar, 100 µm.
(B) Quantification of total apoptotic cells. (C) Cell cycle
distribution (G1, S and G2 phases) was
analyzed using flow cytometry after PI staining. (D) Differences in
cell cycle phase distribution were compared using statistical
analysis and presented as bar charts. Data are presented as mean ±
SD from three independent experiments. PI, propidium iodide; NC,
negative control.

Figure 3

Combination of YY-20394 and ABT199
has a synergistic effect on MV-4-11 cells. The dose-response curves
indicate the percentage growth inhibition of (A) THP-1, (B) U937
and (C) MV-4-11 cells in response to increasing concentrations of
ABT199 for 24 or 48 h, as measured using CCK-8 assays. (D) THP-1,
(E) U937 and (F) MV-4-11 cells were treated with YY-20394, ABT199
alone or YY-20394/ABT199 combination at a constant ratio relative
to the IC50 value for 48 h. Cell inhibition was assessed
using the CCK-8 assay, and CI values were calculated to evaluate
the effects of YY-20394 and ABT199 in three acute myeloid leukemia
cell lines. Data are presented as mean ± SD from three independent
experiments. CCK-8, Cell Counting Kit-8; IC50,
half-maximal inhibitory concentration; Fa, fraction affected; CI,
combination index.

Figure 4

YY-20394 and ABT199 synergistically
promote apoptosis in MV-4-11 cells without inducing cell cycle
arrest. MV-4-11 cells were treated with 120 nM of ABT199, 30 nM of
YY-20394 or a combination of both for 48 h. (A) Early and late
apoptotic cells were assayed using the acridine orange/ethidium
bromide dual staining method. Magnification, ×400; scale bar, 20
µm. (B) Quantification of total apoptotic cells. (C) Cell cycle
distribution (G1, S and G2 phases) was
analyzed using flow cytometry after PI staining and (D) the
statistical results were presented as bar charts. Data are
presented as mean ± SD from three independent experiments. PI,
propidium iodide; NC, negative control.

Figure 5

Effect of YY-20394 and ABT199 on
apoptotic pathways in MV-4-11 cells. MV-4-11 cells were treated
with 120 nM of ABT199, 30 nM of YY-20394 or a combination of both
for 48 h. (A) The mRNA levels of anti-apoptotic factors Mcl-1,
Bcl-2 and Bcl-xL were assessed using RT-qPCR. (B) The mRNA levels
of pro-apoptotic factors Bim, Bak and Bax were assessed using
RT-qPCR. (C) The protein results of Mcl-1, Bcl-2, Bcl-xL, Bim, Bak
and Bax were assessed using western blotting. (D) The protein
levels of Mcl-1, Bcl-2, and Bcl-xL were semi-quantified using
densitometric analysis. (E) The protein levels of Bim, Bak and Bax
were semi-quantified using densitometric analysis. (F) The protein
results of c-Myc were assessed using western blotting and (G) the
statistical result of densitometric analysis. Data are presented as
mean ± SD from three independent experiments. RT-qPCR, reverse
transcription-quantitative PCR; Mcl-1, myeloid cell leukemia-1;
Bim, Bcl-2 interacting mediator of cell death; Bcl-xL, B-cell
lymphoma-extra large; Bak, Bcl-2 antagonist killer 1; Bax, Bcl-2
associated X.

Figure 6

Effect of YY-20394 and ABT199 on
p-AKT and p-ERK signaling pathways in MV-4-11 cells. MV-4-11 cells
were treated with 120 nM of ABT199, 30 nM of YY-20394 or a
combination of both for 48 h. (A) The protein levels of AKT, p-AKT
(Ser473), ERK and p-ERK (Thr202/Tyr204) were examined using western
blot. Densitometric analysis of western blot of (B) AKT, (C) p-AKT,
(D) p-AKT/AKT, (E) ERK, (F) p-ERK and (G) p-ERK/ERK. Data are
presented as mean ± SD from three independent experiments. p-,
phosphorylated.
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Copy and paste a formatted citation
Spandidos Publications style
Geng Y, Zhou L, Lou Y, Chen J, Liu Q, Shen J, Yang Y and Wu W: PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells. Oncol Rep 56: 148, 2026.
APA
Geng, Y., Zhou, L., Lou, Y., Chen, J., Liu, Q., Shen, J. ... Wu, W. (2026). PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells. Oncology Reports, 56, 148. https://doi.org/10.3892/or.2026.9153
MLA
Geng, Y., Zhou, L., Lou, Y., Chen, J., Liu, Q., Shen, J., Yang, Y., Wu, W."PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells". Oncology Reports 56.2 (2026): 148.
Chicago
Geng, Y., Zhou, L., Lou, Y., Chen, J., Liu, Q., Shen, J., Yang, Y., Wu, W."PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells". Oncology Reports 56, no. 2 (2026): 148. https://doi.org/10.3892/or.2026.9153
Copy and paste a formatted citation
x
Spandidos Publications style
Geng Y, Zhou L, Lou Y, Chen J, Liu Q, Shen J, Yang Y and Wu W: PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells. Oncol Rep 56: 148, 2026.
APA
Geng, Y., Zhou, L., Lou, Y., Chen, J., Liu, Q., Shen, J. ... Wu, W. (2026). PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells. Oncology Reports, 56, 148. https://doi.org/10.3892/or.2026.9153
MLA
Geng, Y., Zhou, L., Lou, Y., Chen, J., Liu, Q., Shen, J., Yang, Y., Wu, W."PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells". Oncology Reports 56.2 (2026): 148.
Chicago
Geng, Y., Zhou, L., Lou, Y., Chen, J., Liu, Q., Shen, J., Yang, Y., Wu, W."PI3Kδ inhibitor YY‑20394 is effective alone or in combination with Bcl‑2 inhibitor ABT199 in acute myeloid leukemia cells". Oncology Reports 56, no. 2 (2026): 148. https://doi.org/10.3892/or.2026.9153
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