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

Jurkovic Mlakar, Simona ; Uppugunduri, Satyanarayana Chakradhara Rao ; Nava, Tiago ; Mlakar, Vid ; Golay, Hadrien ; Robin, Shannon ; Waespe, Nicolas ; Rezgui, Mohamed Aziz ; Chalandon, Yves ; Boelens, Jaap Jan ; Bredius, Robert G. M. ; Dalle, Jean-Hugues ; Peters, Christina ; Corbacioglu, Selim ; Bittencourt, Henrique ; Krajinovic, Maja ; Ansari, Marc

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Details

Dokumentenart:	Artikel
Titel eines Journals oder einer Zeitschrift:	Journal of Cancer Research and Clinical Oncology
Verlag:	Springer
Ort der Veröffentlichung:	NEW YORK
Band:	148
Nummer des Zeitschriftenheftes oder des Kapitels:	1
Seitenbereich:	S. 71-86
Datum:	2022
Institutionen:	Medizin > Abteilung für Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation
Identifikationsnummer:	Wert Typ 10.1007/s00432-021-03769-2 DOI
Stichwörter / 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
Dewey-Dezimal-Klassifikation:	600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin
Status:	Veröffentlicht
Begutachtet:	Ja, diese Version wurde begutachtet
An der Universität Regensburg entstanden:	Ja
Dokumenten-ID:	56911

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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 ...

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 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.

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