Chakradhara Rao Uppugunduri Satyanarayana

University of Geneva

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Yves Chalandon

University of Geneva

Henrique Bittencourt

Centre Hospitalier Universitaire Sainte-Justine

Mohamed-Ali Rezgui

Centre Hospitalier Universitaire Sainte-Justine

Christina Peters

St Anna Children's Hospital

Simona Jurković Mlakar

University of Geneva

Vid Mlakar

University of Geneva

Jaap Jan Boelens

Memorial Sloan Kettering Cancer Center

Selim Corbacioglu

University Hospital Regensburg

Jean‐Hugues Dalle

Assistance Publique – Hôpitaux de Paris

Maja Krajinović

Université de Montréal

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University of Geneva

University Hospital of Geneva

Hôpital Beau-Séjour

Centre Hospitalier Universitaire Sainte-Justine

Université de Montréal

Stiftung Liebenau (Germany)

Dana-Farber Cancer Institute

Leiden University Medical Center

Geneva College

Harvard University

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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. On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation

Research Square (Research Square) (2021)

Simona Jurković Mlakar Chakradhara Rao Uppugunduri Satyanarayana Tiago Nava Vid Mlakar Hadrien G. Golay

Abstract BackgroundRelapse 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 null variants of Glutathione S-transferases GSTM1 and GSTT1 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 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. 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. Trial registrationClinicalTrials.gov identifier: NCT01257854, Registered February 2008 – retrospectively registered.

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10.21203/rs.3.rs-439729/v1

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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.

Research Square (Research Square) (2021)

Simona Jurković Mlakar Chakradhara Rao Uppugunduri Satyanarayana Tiago Nava Vid Mlakar Hadrien G. Golay

Abstract Background : 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 null variants of Glutathione S-transferases GSTM1 and GSTT1 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). 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. Trial registration : ClinicalTrials.gov identifier: NCT01257854, Registered February 2008 – retrospectively registered.

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Null cell

10.21203/rs.3.rs-398836/v1

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Potential Predictive Biomarkers used to optimize treatments for Sinusoidal Obstruction Syndrome in pediatric Hematopoietic stem cell transplantation

Patricia Huezo-Diaz Chakradhara Rao Uppugunduri Satyanarayana Marc Ansari

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A bio-chemical Study on Liver Disorders among Jaundice Patients from Coastal Andhra Pradesh, India

M. Kiran Deedi Doss Prakash V Siva Prabodh Reena Nayak Chakradhara Rao Uppugunduri Satyanarayana

Objective: To detect types of liver disorders through biochemical studies in coastal Andhra Pradesh, India. Methods: Serum level of bilirubin (total and direct), serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) and alkaline phosphatase (ALP) were measured among the adult men and women from a South Indian district. Standard methodologies were adopted during selection of study participants and collection and analysis of blood samples. Results: It is observed that there is no difference in the levels of bilirubin (total and direct) and ALP in male and female patients. It is observed that there are significant differences in the levels of SGOT and SGPT. Males recorded higher levels than females. Conclusion: A considerable number of patients showed increased levels of total and direct bilirubin, SGOT, SGPY and ALP. The higher levels of SGOT and SGPT among males might be due to their alcoholic habits and among men in this community. The overall liver function abnormalities may be due to dietary habits, mal-absorption, nonalcoholic fatty liver, diabetes mellitus and contaminated drinking water.

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