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
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...
Gespeichert in:
Veröffentlicht in: | Journal of cancer research and clinical oncology 2022-01, Vol.148 (1), p.71-86 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | 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. |
---|---|
ISSN: | 0171-5216 1432-1335 |
DOI: | 10.1007/s00432-021-03769-2 |