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[Mechanism of Anti Apoptosis and Immune Evasion in Drug-Resistant Leukemia Cells Mediated by STAT3]

Zhu-Xia Jia¹, Xu-Zhang Lu¹, Jin-Yuan He¹

¹Department of Hematology, The Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou 213000, China.

Zhongguo Shi Yan Xue Ye Xue Za Zhi

|December 7, 2020

Abstract

Objective:

To investigate the mechanisms of anti-apoptosis and immune evasion in drug-resistant leukemia cells mediated by STAT3, further to explore the possible mechanism of leukemia relapse caused by minimal residual.

Methods:

Drug-resistance leukemia cell line was established by transfecting pcDNA3.1-STAT3 into K562 cells (K562/STAT3). The expression of STAT3, BAX and NKG2D ligands (MICA and ULBP1) in K562/-cells, K562/STAT3 were detected by Western blot and/or RQ-PCR. Cells apoptosis and the killing effect of NK cells on leukemia cells were detected by flow cytometry.

Results:

The expression of the total STAT3, STAT3 phosphorylation in K562/STAT3 was significantly increased, and P-gp mRNA expression was increased also significantly (P<0.005). In K562/STAT3 cells, the expression of pro-apoptotic BAX (P=0.005) was significantly lower, and the number of apoptotic cells (P=0.002) induced by adriamycin was significantly decreased as compared with those in K562/- cells. After K562/STAT3 cells were treated by STAT3 inhibitor (SH-4-54), the expression of BAX mRNA (P=0.017) was significantly higher and the number of apoptotic cells (P=0.005) was significantly increased. The MICA and ULBP1 mRNA expression in K562/STAT3 cells was significantly lower than that in K562/- cells, and also for MICA and ULBP1 protein (MICA and ULPB1 mRNA: P<0.0001, MICA protein: P=0.001, ULPB1 protein: P=0.022). After K562/STAT3 cells were treated with STAT3 inhibitor (SH-4-54), the expression of MICA mRNA and protein was increased (mRNA: P=0.001, protein: P=0.002), but ULBP1 mRNA and protein showed no significantly change (mRNA: P=0.137, protein: P=0.1905). The cytotoxicity of NK cells to K562/STAT3 cells was susceptible as compared with K562/- (P=0.002), but the cytotoxicity of K562/STAT3 cells to NK cell could be recovered by STAT3 inhibitor (P=0.006).

Conclusion:

STAT3 phosphorylation can inhibits cell apoptosis and promotes cell immune escape. STAT3 inhibitors can promote the apoptosis of leukemia cells and increase their sensitivity to NK cells.

Insights

Signal transducer and activator of transcription 3 (STAT3) phosphorylation promotes leukemia cell survival and immune evasion. STAT3 inhibitors can enhance leukemia cell apoptosis and NK cell-mediated killing, offering potential therapeutic strategies.

Area of Science:

Oncology
Immunology
Molecular Biology

Background:

Leukemia drug resistance and relapse are significant clinical challenges.
Minimal residual disease contributes to leukemia recurrence.
The role of Signal transducer and activator of transcription 3 (STAT3) in leukemia progression requires further elucidation.

Purpose of the Study:

To investigate STAT3-mediated mechanisms of anti-apoptosis in drug-resistant leukemia.
To explore STAT3's role in immune evasion by leukemia cells.
To understand STAT3's contribution to leukemia relapse via minimal residual disease.

Main Methods:

Established a drug-resistant leukemia cell line (K562/STAT3) by transfecting K562 cells with pcDNA3.1-STAT3.
Detected STAT3, BAX, MICA, and ULBP1 expression using Western blot and RQ-PCR.
Assessed apoptosis and NK cell cytotoxicity via flow cytometry.

Main Results:

K562/STAT3 cells showed increased STAT3 phosphorylation, decreased BAX expression, and reduced adriamycin-induced apoptosis.
STAT3 inhibition increased BAX expression and apoptosis in K562/STAT3 cells.
K562/STAT3 cells exhibited lower MICA and ULBP1 expression, reduced NK cell cytotoxicity, and STAT3 inhibition partially restored MICA expression and NK cell activity.

Conclusions:

STAT3 phosphorylation inhibits leukemia cell apoptosis and promotes immune escape.
STAT3 inhibitors can enhance leukemia cell apoptosis and increase sensitivity to NK cell-mediated killing.
Targeting STAT3 may be a viable strategy to overcome drug resistance and prevent leukemia relapse.

Read full analysis

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