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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 × 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.

journal of cancer research and clinical oncology

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