Evaluation of cationic channel TRPV2 as a novel biomarker and therapeutic target in Leukemia-Implications concerning the resolution of pulmonary inflammation

Kodappully S Siveen,Ibrahim A Janahi,Kirti S Prabhu,Shahab Uddin,Martin Steinhoff,Maysaloun Merhi,Fouad Azizi,Mohamed Chikri,Said Dermime,Ramzi M Mohammad,Abdelilah Arredouani,Aeijaz S Parray

doi:10.1038/s41598-018-37469-8

Abstract

Patients treated during leukemia face the risk of complications including pulmonary dysfunction that may result from infiltration of leukemic blast cells (LBCs) into lung parenchyma and interstitium. In LBCs, we demonstrated that transient receptor potential vanilloid type 2 channel (TRPV2), reputed for its role in inflammatory processes, exhibited oncogenic activity associated with alteration of its molecular expression profile. TRPV2 was overexpressed in LBCs compared to normal human peripheral blood mononuclear cells (PBMCs). Additionally, functional full length isoform and nonfunctional short form pore-less variant of TRPV2 protein were up-regulated and down-regulated respectively in LBCs. However, the opposite was found in PBMCs. TRPV2 silencing or pharmacological targeting by Tranilast (TL) or SKF96365 (SKF) triggered caspace-mediated apoptosis and cell cycle arrest. TL and SKF inhibited chemotactic peptide fMLP-induced response linked to TRPV2 Ca2+ activity, and down-regulated expression of surface marker CD38 involved in leukemia and lung airway inflammation. Challenging lung airway epithelial cells (AECs) with LBCs decreased (by more than 50%) transepithelial resistance (TER) denoting barrier function alteration. Importantly, TL prevented such loss in TER. Therefore, TRPV2 merits further exploration as a pharmacodynamic biomarker for leukemia patients (with pulmonary inflammation) who might be suitable for a novel [adjuvant] therapeutic strategy based on TL.

Highlights

Leukemia covers a broad spectrum of hematological neoplasms characterized by profound genetic alterations of the bone marrow hematopoietic precursors which transform into different types of abnormal immature blasts cells exhibiting differentiation arrest, defective apoptosis, and increased proliferative potential[1]
We used reverse transcribed (RT)-qPCR and western blot to determine TRPV2 mRNA transcript expression level in PBMCs collected from healthy donors and LBCs K562, U937, and THP-1 defined elsewhere
Using a set of primers designed to detect all TRPV2 isoforms, we found that total TRPV2 mRNA levels were significantly higher in LBCs compared to normal PBMCs (Fig. 1A)

Summary

Introduction

Leukemia covers a broad spectrum of hematological neoplasms characterized by profound genetic alterations of the bone marrow hematopoietic precursors which transform into different types of abnormal immature blasts cells exhibiting differentiation arrest, defective apoptosis, and increased proliferative potential[1]. There is a good deal of evidence that pulmonary leukemic infiltrates may directly damage airway epithelium and induce an uncontrollable hyperinflammatory reaction in the lung. We brought to light a seemingly fatal complication of leukemia and a new dimension in therapy for [hard to treat] leukemia that can be adopted for resolving [pulmonary] inflammation. To achieve this goal, we sought to identify a marker in leukemic blasts that fulfills criteria such as exhibition of oncogenic capacity, involvement in inflammatory processes (e.g. migration/extravasation), and ideally can be exploited as a therapeutic target

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Results

Discussion

Conclusion