Jurkovic Mlakar, SimonaSimonaJurkovic MlakarUppugunduri, Satyanarayana Chakradhara RaoSatyanarayana Chakradhara RaoUppugunduriNava, TiagoTiagoNavaMlakar, VidVidMlakarGolay, HadrienHadrienGolayRobin, ShannonShannonRobinWaespe Laredo, Nicolas ThomasNicolas ThomasWaespe LaredoRezgui, Mohamed AzizMohamed AzizRezguiChalandon, YvesYvesChalandonBoelens, Jaap JanJaap JanBoelensBredius, Robert G MRobert G MBrediusDalle, Jean-HuguesJean-HuguesDallePeters, ChristinaChristinaPetersCorbacioglu, SelimSelimCorbaciogluBittencourt, HenriqueHenriqueBittencourtKrajinovic, MajaMajaKrajinovicAnsari, MarcMarcAnsari2024-09-022024-09-022022-01https://boris-portal.unibe.ch/handle/20.500.12422/43731PURPOSE This study aimed to retrospectively evaluate the genetic association of null variants of glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with hematological malignancies (HMs) undergoing busulfan (BU)- containing allogeneic hematopoietic stem cell transplantation (HSCT) and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST gene-edited cell models. METHODS GSTM1- and GSTT1-null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1-null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell death studies were conducted in GSTs- null and non-null LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines. RESULTS Carrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76-15.42; p = 1.9 × 10-5]). BU-induced cell death preferentially in THP1GSTM1(non-null) and LCLsGSTM1(non-null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation. CONCLUSION The clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation.enAcute leukemia Busulfan resistance Hematological malignancies Hematopoietic stem cell transplantation Null genotypes of glutathione S-transferases Post-transplant relapse600 - Technology::610 - Medicine & health300 - Social sciences, sociology & anthropology::360 - Social problems & social servicesarticle10.48350/1593493449922210.1007/s00432-021-03769-2