The impact of ICAM-1, CCL2 and TGM2 gene polymorphisms on differentiation syndrome in acute promyelocytic leukemia.
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.
['Mohammadzadeh|Zahra|Z|', 'Omidkhoda|Azadeh|A|', 'Chahardouli|Bahram|B|', 'Hoseinzadeh|Ghazaleh|G|', 'Moghaddam|Kamran Ali|KA|', 'Mousavi|Seyed Asadollah|SA|', 'Rostami|Shahrbano|S|']
D058186:Acute Kidney Injury D000328:Adult D000970:Antineoplastic Agents D014408:Biomarkers, Tumor D016022:Case-Control Studies D002454:Cell Differentiation D018932:Chemokine CCL2 D005260:Female D005500:Follow-Up Studies D019204:GTP-Binding Proteins D006801:Humans D018799:Intercellular Adhesion Molecule-1 D015473:Leukemia, Promyelocytic, Acute D008171:Lung Diseases D008297:Male D011110:Polymorphism, Genetic D011379:Prognosis D000091345:Protein Glutamine gamma Glutamyltransferase 2 D015996:Survival Rate D013577:Syndrome D018746:Systemic Inflammatory Response Syndrome D011503:Transglutaminases D014212:Tretinoin
ICAM-1 Differentiation syndrome Acute Promyelocytic leukemia SNPs CCL2 chemokine Transglutaminase II