The impact of ICAM-1, CCL2 and TGM2 gene polymorphisms on differentiation syndrome in acute promyelocytic leukemia

Abstract

Background Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are well-tolerated and effective treatments for Acute Promyelocytic Leukemia (APL), Differentiation Syndrome (DS) is a lethal side effect in some patients. The pathogenesis of DS is complex and not well understood; however, it is considered as an inflammatory response due to cytokines release of differentiated cells. Moreover, adhesion molecules that are widely expressed on the surface of differentiated cells and gene expression changes of transglutaminase2 (TGM2) are mechanisms involved in the development of DS. The purpose of this study was to assess the association of single nucleotide polymorphisms (SNP) of Intercellular Adhesion Molecule-1 (ICAM-1), chemokine (C-C motif) ligand 2 (CCL2) and TGM2 as inflammatory factors with differentiation syndrome susceptibility. Methods DNA was extracted from 133 APL patients and 100 normal controls. Assessment according to the PETHEMA criteria revealed that 13.5% of these patients experienced differentiation syndrome. Tetra-ARMS PCR and PCR-RFLP were done to amplify DNA fragments in APL patients with and without DS. Then DNA sequencing was done to validate the results. SNPStats, SPSS and Finch TV were used to analyze the results. Results A significant correlation was found between rs4811528 in the TGM2 gene and differentiation syndrome susceptibility (P = 0.002, 95% CI = 1.74–18.81, OR = 5.72) while rs5498 in ICAM-1, rs1024611 in CCL2, and rs7270785 in TGM2 genes showed no correlation with differentiation syndrome. The G allele of rs7270785 and rs4811528 showed a haplotypic association with differentiation syndrome (P = 0.03, 95% CI = 1.13–13.86, OR = 3.96). Conclusions AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.

Roles of PADI4 in the expression of cytokines involved in inflammation and adhesion in differentiated NB4 cells treated with ATRA

“…However, several patient may experience DS (21). Although the pathogenesis of DS remains to be elucidated, mounting evidence has suggested that sustained hyperinflammation serves a critical role in its pathogenesis (16,21,22). The current study showed that PADI4 could serve an essential role in regulating the expression of inflammatory cytokines, such as TNF-α and IL-1β, in ATRA-treated NB4 cells.…”

The role of transglutaminase 2 in regulation of the balance between autophagy and apoptosis in tumor cells

“…Уровень этого фермента коррелировал с экспрессией молекул адгезии и рядом апоптотических белков [113]. В другом исследовании на образцах пациентов с острым промиелоцитарным лейкозом продемонстрирована положительная корреляция между экспрессией TG2 и синдромом дифференцировки, возникающим при терапии триоксидом свинца и транс-ретиноевой кислотой [114].…”

The Role of Transglutaminase 2 in Cancer: An Update

“…When it is not rapidly diagnosed and treated, APL is considered one of the worst leukemias [ 93 ]. In the context of canonical APL treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), TG2 expression is increased, and this leads to an intensification of inflammation through the NF-κB pathway [ 94 ]. Consequently, TG2 inhibition reduces ROS production, inflammation processes, and consequent organ damage [ 95 ].…”

“…Consequently, TG2 inhibition reduces ROS production, inflammation processes, and consequent organ damage [ 95 ]. To turn off the lethal effects of the inflammatory response (called differentiation syndrome, it is typically present after ATRA-ATO treatment [ 96 ]) is crucial to improving patient outcome [ 94 ]. Moreover, Jambrovics K et al highlight the mechanism through which TG2 is able to extend APL cell survival following conventional ATRA-ATO treatment.…”