Lyn mediates FIP1L1-PDGFRA signal pathway facilitating IL-5RA intracellular signal through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex in CEL.

Bin Li,Yeping Dong,Zhenzi Peng,Ruijuan Li,Chunfang Zhang,Yuexiang Wang,Jun Wang,Cui Li,Zhengxi He,Nacef Bahri,Chaojun Duan,Quan Wang,Guangsen Zhang,Jie Qiong Tan,Jingchen Lu

doi:10.18632/oncotarget.11401

Abstract

The Fip1-like1 (FIP1L1)–platelet-derived growth factor receptor alpha (PDGFRA) (F/P) oncogene can cause chronic eosinophilic leukemia (CEL), but requires IL-5 cytokine participation. In this study, we investigate the mechanism of F/P in collaboration with IL-5 in CEL. The results showed that Lyn, a key effector in the IL-5-motivated eosinophil production, is extensively activated in F/P-positive CEL cells. Lyn can associate and phosphorylate IL-5 receptor α (IL-5RA) in F/P-positive cells. Moreover, the activation of Lyn and IL-5R kinase were strengthened when the cells were stimulated by IL-5. Lyn inhibition in F/P-positive CEL cells attenuated cellular proliferation, induced apoptosis, and blocked cell migration and major basic protein (MBP) release. We identified the FIP1L1-PDGFRA/JAK2/Lyn/Akt complex in the F/P-expressing cells which can be disrupted by dual inhibition of JAK2 and Lyn, repressing cell proliferation in both EOL-1(F/P-positive human eosinophilic cell line) and imatinib-resistance (IR) cells. Altogether, our data demonstrate that Lyn is a vital downstream kinase activated by F/P converged with IL-5 signals in CEL cells. Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.

Highlights

Hypereosinophilic syndrome (HES) is defined as an unexplained persistent eosinophilia exceeding 1500/ mm3 eosinophils per liter for more than 6 months in combination with symptoms and signs of organ damage resulting from eosinophil infiltration
The results demonstrated that phospho-Lyn level was gradually reduced in the F/P(+) chronic eosinophilic leukemia (CEL) cases and EOL-1 cells with phospho-F/P inhibited by imatinib (Figure 1), which suggested Lyn kinase is the target of F/P oncoprotein
The whole CEL characteristics with eosinophiliaassociated end-organ infiltration needs oncoprotein F/P collaborated with additional IL-5 stimulation [4, 21]

Summary

Introduction

Hypereosinophilic syndrome (HES) is defined as an unexplained persistent eosinophilia exceeding 1500/ mm eosinophils per liter for more than 6 months in combination with symptoms and signs of organ damage resulting from eosinophil infiltration. It includes different types of hematologic diseases with male predominance and age distribution of 20–50 year-old. The FIP1L1-PDGFRA fusion gene(F/P) induces constitutive PDGFRA kinase activation, and exists in about 10–20% of HES/CEL [1]. Introduction of interleukin-5 (IL-5) was necessary to recapitulate typical features of HES/CEL, including hyper eosinophilia and tissue infiltration of eosinophils when coexpressed with F/P fusion gene [4].

Methods

Results

Conclusion