scholarly journals 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

2021 ◽  
Author(s):  
Simona Jurkovic Mlakar ◽  
Chakradhara Rao Uppugunduri Satyanarayana ◽  
Tiago Nava ◽  
Vid Mlakar ◽  
Hadrien Golay ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
Hematopoietic Stem ◽  
The Impact

Abstract 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 THP1GSTM1(non−null) and LCLsGSTM1(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.

scholarly journals 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.

2021 ◽  
Author(s):  
Simona Jurkovic Mlakar ◽  
Chakradhara Rao Uppugunduri Satyanarayana ◽  
Tiago Nava ◽  
Vid Mlakar ◽  
Hadrien Golay ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
Leukemia Cell ◽  
Hematopoietic Stem ◽  
Glutathione S Transferases ◽  
The Impact

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 THP1GSTM1(non-null) and LCLsGSTM1(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.

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

2021 ◽  
Author(s):  
Simona Jurkovic Mlakar ◽  
Chakradhara Rao Uppugunduri Satyanarayana ◽  
Tiago Nava ◽  
Vid Mlakar ◽  
Hadrien Golay ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
Leukemia Cell ◽  
Hematopoietic Stem ◽  
Glutathione S Transferases ◽  
The Impact

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.MethodsGSTM1- 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. ResultsCarrying 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 THP1GSTM1(non-null) and LCLsGSTM1(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.

scholarly journals The Impact of Allogeneic Hematopoietic Stem Cell Transplantation on Kidney Function in Children—A Single Center Experience

2021 ◽  
Vol 10 (5) ◽  
pp. 1113
Author(s):  
Kinga Musiał ◽  
Krzysztof Kałwak ◽  
Danuta Zwolińska
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Serum Creatinine ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Kidney Function ◽  
Hematopoietic Stem ◽  
Oncological Patients ◽  
The Impact

Background: Knowledge about the impact of allogeneic hematopoietic stem cell transplantation (alloHSCT) on renal function in children is still limited. Objectives: The aim of the study was to evaluate kidney function in children undergoing alloHSCT, with special focus on differences between patients transplanted due to oncological and non-oncological indications. Materials and Methods: The data of 135 children undergoing alloHSCT were analyzed retrospectively. The serum creatinine and estimated glomerular filtration rate (eGFR) values were estimated before transplantation at 24 h; 1, 2, 3, 4 and 8 weeks; and 3 and 6 months after alloHSCT. Then, acute kidney injury (AKI) incidence was assessed. Results: Oncological children presented with higher eGFR values and more frequent hyperfiltration rates than non-oncological children before alloHSCT and until the 4th week after transplantation. The eGFR levels rose significantly after alloHSCT, returned to pre-transplant records after 2–3 weeks, and decreased gradually until the 6th month. AKI incidence was comparable in oncological and non-oncological patients. Conclusions: Children undergoing alloHSCT due to oncological and non-oncological reasons demonstrate the same risk of AKI, but oncological patients may be more prone to sustained renal injury. Serum creatinine and eGFR seem to be insufficient tools to assess kidney function in the early post-alloHSCT period, when hyperfiltration prevails, yet they reveal significant differences in long-term observation.

The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2003-2008 ◽  
Author(s):  
Michael Boeckh ◽  
W. Garrett Nichols
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cohort Studies ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Preemptive Therapy ◽  
Prevention Strategies ◽  
Hematopoietic Stem ◽  
The Impact

AbstractIn the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell–depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.

scholarly journals SECOND ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES

2019 ◽  
Vol 64 (1) ◽  
pp. 35-48
Author(s):  
L. A. Kuzmina ◽  
Z. V. Konova ◽  
E. N. Parovichnikova ◽  
M. Y. Drokov ◽  
V. A. Vasilyeva ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Failure ◽  
Hematological Malignancies ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem

Background.Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a standard treatment for many patients with hematological malignancies. Complications of allo-HSCT are frequently associated either with a relapse of the underlying disease or a graft failure. Second transplantation can be offered to selected patients and is seen as the only curative option. In this paper, we report the experience of managing 24 such patients, all of whom underwent a second allo-HSCT.Patients and methods.The research involved 24 patients (12 males/12 females) suffering from acute myeloid leukemia (AML, n = 14), acute lymphoblastic leukemia (ALL, n = 4), myeloproliferative disease (MPD, n = 3) and myelodysplastic syndrome (MDS, n = 3). The patients’ age ranged from 18 to 56 years, with the median age being 32 years. All the patients underwent a second allo-HSCT due to the disease relapse (n = 11) or graft failure (n = 13). 12 patients underwent a second allo-HSCT within the period of less than 6 months after the first allo-HSCT.Results.Following the second allo-HSCT, engraftment occurred in 18/24 (75 %) patients, while 3 patients demonstrated graft failure and 3 — disease progression. Out of 18 patients having engrafted, 9 (50%) died during the first 100 days after allo-HSCT as a result of severe infections or visceral toxicity. 3 more lethal outcomes were recorded in later periods due to the disease progression. The overall mortality rate after the second allo-HSCT equalled 61.5 %. The median overall survival (OS) and disease-free survival (DFS) rates were 13.5 months and 10.59 months, respectively. Three-year OS and DFS were 38.5 % and 27.6 % respectively. Significant differences in terms of OS were detected for patients with a longer interval (>6 months) between the first and second allo-HSCT. The change of a donor was not associated with a better clinical outcome.

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