PAK1 Mediates Bone Marrow Stromal Cell-Induced Drug Resistance in Acute Myeloid Leukemia via ERK1/2 Signaling Pathway

Banban Li; Ruinan Jia; Wei Li; Ying Zhou; Dongmei Guo; Qingliang Teng; Shenghong Du; Mingying Li; Wěi Li; Tao Sun; Daoxin Ma; Min Ji; Chunyan Ji

doi:10.3389/fcell.2021.686695

PAK1 Mediates Bone Marrow Stromal Cell-Induced Drug Resistance in Acute Myeloid Leukemia via ERK1/2 Signaling Pathway

Front Cell Dev Biol. 2021 Jul 8:9:686695. doi: 10.3389/fcell.2021.686695. eCollection 2021.

Authors

Banban Li^{1

2}, Ruinan Jia¹, Wei Li¹, Ying Zhou¹, Dongmei Guo², Qingliang Teng², Shenghong Du^{1

2}, Mingying Li¹, Wěi Li¹, Tao Sun^{1

3}, Daoxin Ma^{1

3}, Min Ji¹, Chunyan Ji¹

Affiliations

¹ Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Department of Hematology, Taian City Central Hospital, Taian, China.
³ Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China.

Abstract

Background: Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and bone marrow stromal cells (BMSCs) protect leukemia cells from chemotherapy eventually leading to recurrence. This study was designed to investigate the role of p21-activated kinase 1 (PAK1) in AML progression and chemosensitivity, highlighting the mechanism of stroma-mediated chemoresistance.

Methods: The GEPIA and TCGA datasets were used to analyze the relationship between PAK1 mRNA expression and various clinical parameters of AML patients. Cell proliferation and apoptosis were examined to evaluate the role of PAK1 on chemosensitivity in AML by silencing PAK1 with shRNA or small molecular inhibitor. Human BMSC (HS-5) was utilized to mimic the leukemia bone marrow microenvironment (BMM) in vitro, and co-culture model was established to investigate the role of PAK1 in BMSC-mediated drug resistance.

Results: p21-activated kinase 1 high expression was shown to be associated with shorter overall survival in AML patients. The silence of PAK1 could repress cell proliferation, promote apoptosis, and enhance the sensitivity of AML cells to chemotherapeutic agents. More importantly, BMSCs induced PAK1 up-regulation in AML cells, subsequently activating the ERK1/2 signaling pathway. The effect of BMSC-mediated apoptotic-resistance could be partly reversed by knock down of PAK1.

Conclusion: p21-activated kinase 1 is a potential prognostic predictor for AML patients. PAK1 may play a pivotal role in mediating BMM-induced drug resistance, representing a novel therapeutic target in AML.

Keywords: ERK1/2; acute myeloid leukemia; bone marrow stromal cell; drug resistance; p21-activated kinase 1.