GSTM1 and GSTT1 Double Null Genotypes Determining Cell Fate and Proliferation as Potential Risk Factors of Relapse in Children with Hematological Malignancies after Stem Cell Transplantation.
Bibliographic record
Abstract
<title>Abstract</title> <bold>Background</bold>: Relapse is the major cause of treatment failure in children with hematological malignancies (HMs) undergoing busulfan (BU)- based allogeneic hematopoietic stem cell transplantation (HSCT). Glutathione S-transferases (GSTs) isoforms that participate in BU detoxification and protect cells against stress and cell death may be linked to post-HSCT outcomes. This study aimed to retrospectively evaluate the genetic association of <italic>null</italic> variants of Glutathione S-transferases <italic>GSTM1 </italic>and <italic>GSTT1</italic> with relapse incidence in children with HMs undergoing BU- containing allogeneic HSCT and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized and tumor lymphoblastoid cell lines (LCLs).<bold>Methods</bold>: <italic>GSTM1- and GSTT1- null</italic> alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of <italic>GSTM1-</italic> and <italic>GSTT1- null</italic> variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell-death studies were conducted in <italic>GSTs</italic>- <italic>null</italic> and <italic>non-null</italic> LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines. <bold>Results</bold>: <italic>Carrying GSTM1/GSTT1 double null genotype was found to be an</italic> 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<sup>-5</sup>]). BU induced cell death preferentially in THP1<sup><italic>GSTM1(non-null)</italic></sup> and LCLs<sup><italic>GSTM1(non-null)</italic></sup> as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to <italic>null</italic> cells, while <italic>GSTT1</italic> <italic>non-null</italic> cells showed increased baseline proliferation. <bold>Conclusion</bold>: The clinical association suggests that <italic>GSTM1</italic>/<italic>GSTT1 double null genotype </italic>could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that <italic>GSTM1</italic> status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation. <bold>Trial registration</bold>: ClinicalTrials.gov identifier: NCT01257854, Registered February 2008 – retrospectively registered.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".