Mlakar, Simona Jurkovic and Satyanarayana, Chakradhara Rao Uppugunduri and Nava, Tiago and Mlakar, Vid and Golay, Hadrien and Robin, Shannon and Waespe, Nicolas and Rezgui, Mohamed-Ali and Chalandon, Yves and Boelens, Jaap Jan and Bredius, Robert G. M. and Dalle, Jean-Hugues and Peters, Christina and Corbacioglu, Selim and Bittencourt, Henrique and Krajinovic, Maja and Ansari, Marc (2022) GSTM1 and GSTT1 double null genotypes determining cell fate and proliferation as potential risk factors of relapse in children with hematological malignancies after hematopoietic stem cell transplantation. JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 148 (1). pp. 71-86. ISSN 0171-5216, 1432-1335
Full text not available from this repository. (Request a copy)Abstract
Purpose 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 x 10(-5)]). BU-induced cell death preferentially in THP1(GSTM1(non-null)) and LCLs(GSTM1(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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GLUTATHIONE-S-TRANSFERASES; ACUTE LYMPHOBLASTIC-LEUKEMIA; BUSULFAN PHARMACOKINETICS; INTRAVENOUS BUSULFAN; PEDIATRIC-PATIENTS; ADULT PATIENTS; POLYMORPHISMS; CHILDHOOD; GSTT1; DELETIONS; Null genotypes of glutathione S-transferases; Acute leukemia; Hematological malignancies; Hematopoietic stem cell transplantation; Post-transplant relapse; Busulfan resistance |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Sep 2022 09:53 |
| Last Modified: | 27 Sep 2022 09:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48057 |
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