Dasatinib and interferon alpha synergistically induce pyroptosis-like cell death in philadelphia chromosome positive acute lymphoblastic leukemia

Yang Dai; Jingcao Huang; Pu Kuang; Yiguo Hu; Qiang Zeng; Wanhua Zhang; He Li; Fangfang Wang; Tingting Guo; Dan Zhang; Dongni Yi; Yuhuan Zheng; Ting Liu

Dasatinib and interferon alpha synergistically induce pyroptosis-like cell death in philadelphia chromosome positive acute lymphoblastic leukemia

Am J Cancer Res. 2022 Jun 15;12(6):2817-2832. eCollection 2022.

Authors

Yang Dai^{1

2}, Jingcao Huang^{1

2}, Pu Kuang^{1

2}, Yiguo Hu^{2

3}, Qiang Zeng^{1

2}, Wanhua Zhang^{1

2}, He Li^{1

2}, Fangfang Wang^{1

2}, Tingting Guo², Dan Zhang², Dongni Yi¹, Yuhuan Zheng^{1

2

3}, Ting Liu^{1

2}

Affiliations

¹ Department of Hematology, West China Hospital, Sichuan University Chengdu 610041, Sichuan, China.
² Institute of Hematology, West China Hospital, Sichuan University Chengdu 610041, Sichuan, China.
³ State Key Laboratory of Biotherapy, Sichuan University Chengdu 610041, Sichuan, China.

PMID: 35812060
PMCID: PMC9251703

Abstract

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.

Keywords: Philadelphia chromosome-positive acute lymphoblastic leukemia; dasatinib; interferon-α; maintenance therapy; pyroptosis.