Association of CTH variant with sinusoidal obstruction syndrome in children receiving intravenous busulfan and cyclophosphamide before hematopoietic stem cell transplantation

P Huezo-Diaz Curtis, C R S Uppugunduri, J Muthukumaran, M A Rezgui, C Peters, P Bader, M Duval, H Bittencourt, Maja Krajinovic, Marc Ansari, P Huezo-Diaz Curtis, C R S Uppugunduri, J Muthukumaran, M A Rezgui, C Peters, P Bader, M Duval, H Bittencourt, Maja Krajinovic, Marc Ansari

Abstract

Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT) that can be fatal, often attributed to the conditioning regimen prior to HSCT. We evaluated the association of SOS risk with gene variants in cystathionase (CTH), an enzyme involved in glutathione synthesis, in 76 children receiving intravenous busulfan (Bu) before HSCT. Our results indicated an association with CTHc.1364 G>T (ORTT=10.6, 95% confidence interval (CI)=2.16, 51.54) and SOS risk, which was sex dependent (female patients, ORTT=21.82, 95% CI=3.590-132.649). The interaction between CTHc.1364 G>T and another risk variant (GSTA1*B) was explored. A recessive model with the use of GSTA1*B*B and CTH c.1364 TT genotypes proved to be useful at predicting SOS occurrence, indicating the possibility of using these gene variants as markers of SOS occurrence and to further individualize preemptive treatment aimed at reducing SOS incidence.

Trial registration: ClinicalTrials.gov NCT01257854.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A simple diagram to describe the depletion of glutathione (GSH) when busulfan (Bu) is administered first before cyclophosphamide (Cy) and the role of glutathione S-transferase alpha 1 (GSTA1) and cystathionine gamma-lyase (CTH) within this hypothesis of sinosoidal obstruction syndrome (SOS) risk. (a) Shows the main Bu metabolic pathway, where Bu conjugates with GSH and where GSTA1 is the main catalytic enzyme. (b) Shows the transulfuration pathway where methionine is converted to cysteine, the main rate-limiting step for the formation of GSH. CTH is needed for the conversion of cystathionine into cysteine, which is one of the components of GSH. (c) Shows the main Cy metabolic pathway and its metabolites acrolein and 4-hydroxycyclophosphamide, two compounds known to be toxic to liver cells.
Figure 2
Figure 2
Association of sinosoidal obstruction syndrome (SOS) risk with CTH c.1364G>T. The plot shows the number of patients in each curve with and without CTH c.1364 TT and the number of individuals with SOS given in parenthesis. The P-value is shown above the curves, estimated by log-rank test for the cumulative SOS incidence between the genotype groups. Risk of SOS associated with CTH TT carriers in expressed as hazard ratio (HR) with 95% confidence interval (CI) indicated below the plot. HSCT, hematopoietic stem cell transplantation.
Figure 3
Figure 3
Association of sinosoidal obstruction syndrome (SOS) risk with different combinations of GSTA1*B and CTH c.1364G>T or alone. The plots show the number of patients in each curve with GSTA1*B (a), CTH c.1364 TT (b), GSTA1*B and or CTH c.1324 TT (c), GSTA1*B and CTH c.1324 TT (d) and the number of individuals with SOS is given in the parenthesis. The P-value is shown above the curves, estimated by log-rank test for cumulative SOS incidence between the genotype groups. Risk of SOS associated is expressed as hazard ratio (HR) with 95% confidenc interval (CI) indicated below the plot for each.
Figure 4
Figure 4
Binding orientation of cystathionine with cystathionine gamma-lyase (CTH). Two-dimensional representation of CTH (native (a) and mutant (b)) with substrate. The three-dimensional representation of protein–ligand complex was prepared by PyMOL. The LigPlot shows the amino-acid residues of target enzyme around the ligand molecule with hydrogen bond and hydrophobic contacts.

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