Abstract
PurposeThis 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.MethodsGSTM1- 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.ResultsCarrying 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.ConclusionThe 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.
Highlights
Survival rates of children with hematological malignancies (HMs) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) have improved over the years achievingExtended author information available on the last page of the article91% estimated 2-year overall survival
Risk factors that influence transplant success are on the one hand host- and disease related, such as disease genetics and remission status before HSCT, and on the other hand, transplant related, such as conditioning regimen and treatment-related toxicities including for example severe graft-versus-host disease (GvHD), sinusoidal obstruction syndrome (SOS), and infections
In acute lymphoblastic leukemia (ALL), the recently published results showed lower rates of relapse after TBIcontaining conditioning, the results obtained with BU in association with FLU and thiotepa were encouraging and indicate an opportunity to find genetic subgroups of patients who might benefit from the total body irradiation (TBI)-free conditioning (Peters et al 2021)
Summary
Survival rates of children with hematological malignancies (HMs) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) have improved over the years achievingExtended author information available on the last page of the article91% estimated 2-year overall survival. Survival rates of children with hematological malignancies (HMs) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) have improved over the years achieving. The incidence of post-HSCT relapse remains a significant complication and varies from 12 to 33% after 2 years (Peters et al 2021). At least in acute myeloid leukemia (AML), BU has shown lower long-term adverse effects, replacing total body irradiation (TBI) in the conditioning regimen (Lee et al 2020). In acute lymphoblastic leukemia (ALL), the recently published results showed lower rates of relapse after TBIcontaining conditioning, the results obtained with BU in association with FLU and thiotepa were encouraging and indicate an opportunity to find genetic subgroups of patients who might benefit from the TBI-free conditioning (Peters et al 2021)
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