Targeting STAT5 abrogates survival signaling and sensitizes chronic lymphocytic leukemia cells to BCL-2 and MCL-1 inhibition
Abstract
STAT5 is constitutively activated in several hematologic malignancies, where it promotes cell survival. In chronic lymphocytic leukemia (CLL), although STAT5b levels are elevated in leukemic cells from CLL patients compared with healthy controls, the functional significance and mechanistic role of STAT5 remains poorly understood. In this study, we knocked down both STAT5A and STAT5B using lentivirus-mediated shRNA. Loss of STAT5 significantly inhibited CLL cell viability and induced apoptosis. Mechanistically, STAT5 depletion markedly attenuated the activation of the pro-survival AKT and ERK signaling pathways and reduced the expression of the anti-apoptotic proteins MCL-1 and BCL-2, indicating that STAT5 is important for CLL cell survival and represents a potential therapeutic target. Consistently, pharmacological inhibition of STAT5 with the small-molecule compound AC-4-130 significantly suppressed cell viability and promoted apoptosis in CLL cells, accompanied by diminished AKT and ERK signaling and reduced MCL-1 and BCL-2 expression. Furthermore, AC-4–130 in combination with the BCL-2 inhibitor ABT-199 or the MCL-1 inhibitor A-1210477 induced greater CLL cell apoptosis in a dose- and patient-dependent manner. Collectively, these findings demonstrate that STAT5 confers a survival advantage on CLL cells and that its depletion or inhibition triggers apoptosis, providing a preclinical rationale for testing STAT5 inhibitors in combination therapy for CLL.
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BibTeX
@article{shao2026targeting,
title = {{Targeting STAT5 abrogates survival signaling and sensitizes chronic lymphocytic leukemia cells to BCL-2 and MCL-1 inhibition}},
author = {Xiaoya Shao and Shihao Liang and Xueqiong Meng and Jiangqin Jiao and Ying Cui and Jie Sun and David Lubasi Nalisa and Dasaradha Somarouthu and Salvador Macip and Yixiang Chen},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1965206},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1965206},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting STAT5 abrogates survival signaling and sensitizes chronic lymphocytic leukemia cells to BCL-2 and MCL-1 inhibition
AU - Xiaoya Shao
AU - Shihao Liang
AU - Xueqiong Meng
AU - Jiangqin Jiao
AU - Ying Cui
AU - Jie Sun
AU - David Lubasi Nalisa
AU - Dasaradha Somarouthu
AU - Salvador Macip
AU - Yixiang Chen
PY - 2026
DA - 2026/11/09
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1965206
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1965206
AB - STAT5 is constitutively activated in several hematologic malignancies, where it promotes cell survival. In chronic lymphocytic leukemia (CLL), although STAT5b levels are elevated in leukemic cells from CLL patients compared with healthy controls, the functional significance and mechanistic role of STAT5 remains poorly understood. In this study, we knocked down both STAT5A and STAT5B using lentivirus-mediated shRNA. Loss of STAT5 significantly inhibited CLL cell viability and induced apoptosis. Mechanistically, STAT5 depletion markedly attenuated the activation of the pro-survival AKT and ERK signaling pathways and reduced the expression of the anti-apoptotic proteins MCL-1 and BCL-2, indicating that STAT5 is important for CLL cell survival and represents a potential therapeutic target. Consistently, pharmacological inhibition of STAT5 with the small-molecule compound AC-4-130 significantly suppressed cell viability and promoted apoptosis in CLL cells, accompanied by diminished AKT and ERK signaling and reduced MCL-1 and BCL-2 expression. Furthermore, AC-4–130 in combination with the BCL-2 inhibitor ABT-199 or the MCL-1 inhibitor A-1210477 induced greater CLL cell apoptosis in a dose- and patient-dependent manner. Collectively, these findings demonstrate that STAT5 confers a survival advantage on CLL cells and that its depletion or inhibition triggers apoptosis, providing a preclinical rationale for testing STAT5 inhibitors in combination therapy for CLL.
SN - 1663-9812
ER -