Page 99 - 2019_03-Haematologica-web

Acute Myeloid Leukemia
Transglutaminase 2 programs differentiating acute promyelocytic leukemia cells in all-trans retinoic acid treatment to inflammatory stage through NF-κB activation
Ferrata Storti Foundation
Károly Jambrovics,1 Iván P. Uray,2 Zsolt Keresztessy,1,3 Jeffrey W. Keillor,4 László Fésüs1,5 and Zoltán Balajthy1
1Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Hungary; 2Department of Clinical Oncology, Faculty of Medicine, University of Debrecen, Hungary; 3Genome Medicine and Bioinformatics Core Facility, Research Center for Molecular Medicine, University of Debrecen, Hungary; 4Department of Chemistry and Biomolecular Sciences, University of Ottawa, ON Canada and 5MTA DE Apoptosis, Genomics and Stem Cell Research Group of the Hungarian Academy of Sciences, University of Debrecen, Hungary
Haematologica 2019 Volume 104(3):505-515
ABSTRACT
Differentiation syndrome (DS) is a life-threatening complication arising during retinoid treatment of acute promyelocytic leukemia (APL). Administration of all-trans retinoic acid leads to significant changes in gene expression, among the most induced of which is transglutaminase 2, which is not normally expressed in neu- trophil granulocytes. To evaluate the pathophysiological function of transglutaminase 2 in the context of immunological function and disease outcomes, such as excessive superoxide anion, cytokine, and chemokine production in differentiated NB4 cells, we used an NB4 transglutaminase knock-out cell line and a transglutaminase inhibitor, NC9, which inhibits both transamidase- and guanosine triphosphate-binding activities, to clarify the contribution of transglutaminase to the development of potentially lethal DS during all-trans retinoic acid treatment of APL. We found that such treatment not only enhanced cell-surface expression of CD11b and CD11c but also induced high-affinity states; atypical transg- lutaminase 2 expression in NB4 cells activated the nuclear factor kappa (κ)-light-chain-enhancer of the activated B-cell pathway, driving patho- genic processes with an inflammatory cascade through the expression of numerous cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1b), and monocyte chemoattractant protein 1. NC9 decreased the amount of transglutaminase 2, p65/RelA, and p50 in dif- ferentiated NB4 cells and their nuclei, leading to attenuated inflammato- ry cytokine synthesis. NC9 significantly inhibits transglutaminase 2 nuclear translocation but accelerates its proteasomal breakdown. This study demonstrates that transglutaminase 2 expression induced by all- trans retinoic acid treatment reprograms inflammatory signaling net- works governed by nuclear factor κ-light-chain-enhancer of activated B- cell activation, resulting in overexpression of TNF-α and IL-1b in differ- entiating APL cells, suggesting that atypically expressed transglutami- nase 2 is a promising target for leukemia treatment.
Introduction
Acute promyelocytic leukemia (APL), an acute myeloid leukemia (AML) sub- type, is identified by clonal proliferation of promyelocytic precursor cells with reduced ability to differentiate into mature neutrophil granulocytes.1-6 Expression of PML/RARα in APL suppresses differentiation along the neutrophil lineage.7-9 In clinical settings, the target is primarily the PML/RARα chimeric protein and its degradation, initiated by all-trans retinoic acid (ATRA) or arsenic trioxide.10-12 ATRA-induced differentiation therapy leads to differentiation syndrome (DS), which can be fatal in 2.5-30% of cases. DS is characterized by large numbers of
Correspondence:
ZOLTAN BALAJTHY
balajthy@med.unideb.hu
Received: March 6, 2018.
Accepted: September 19, 2018. Pre-published: September 28, 2018.
doi:10.3324/haematol.2018.192823
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/505
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(3)
505
ARTICLE