Targeting STAT5 abrogates survival signaling and sensitizes chronic lymphocytic leukemia cells to BCL-2 and MCL-1 inhibition

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.