CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

O’Driscoll, Mark; Jeggo, Penny A.

doi:10.1038/bmt.2008.18

Cited by 31 publications

(30 citation statements)

References 44 publications

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“…7 In addition, tissue damage as induced by radiochemotherapy in the context of hematopoietic cell transplantation (HCT) may be poorly tolerated, as noted in other disorders due to DNA repair defects, such as in Fanconi anemia and Nijmegen breakage syndrome. [8][9][10][11][12] In fact, a report of 18 ARTEMIS-deficient SCID patients of Native American descent found poorer outcome and lack of secondary teeth in those patients treated with alkylating agents. 13 Also, analysis of 90 SCID patients with different molecular defects found that patients with ARTEMIS deficiency were at higher risk for late complications.…”

Section: Introductionmentioning

confidence: 99%

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID

Schuetz¹,

Neven

Dvorak

et al. 2014

Blood

155

144

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A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T−B−NK+SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T−B−NK+SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

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Section: Introductionmentioning

confidence: 99%

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID

Schuetz¹,

Neven

Dvorak

et al. 2014

Blood

155

144

View full text Add to dashboard Cite

show abstract

“…To some extent, this is reminiscent of the known poorer prognosis for HSCT in Fanconi anemia 21 and DNA ligase IV. 22 Confirming these findings will require more data on the long-term outcome of greater numbers of patients with SCID Artemis who received a transplant. 23 Further efforts should thus be made to design an appropriate strategy or perhaps consider an alternative approach, such as gene therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic GVHD, Ͻ 2 y 24 (27) Severe events after HSCT, < 2 y Persistent diarrhea, Ͼ 1 y With GVHD 20 (22) Without GVHD 9 (10) Autoimmunity 6 (7)…”

Section: Grade 4mentioning

confidence: 99%

Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency

Neven

Leroy

Decaluwe

et al. 2009

Blood

221

242

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“…16,17 Also, transplantation may be followed by prophylaxis of graft-versus-host disease using agents that also have the potential to induce DNA DSBs. 18 RS-SCID and RS-CID patients receive a higher transplantation priority and adjusted pre-and post-transplantation treatment regimens. These regimens involve reduced doses of radiomimetic drugs and/or alternative drugs reported to be efficacious in these patients.…”

mentioning

confidence: 99%

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Lobachevsky

Woodbine

Hsiao

et al. 2015

The Journal of Molecular Diagnostics

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Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of g histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. Severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) are rare genetic disorders. The incidence of SCID in Australia is 1 in 69,000 live births, 1 comparable to the reported incidence of 1 in 100,000 births worldwide. CID patients have increased susceptibility to invasive and opportunistic bacterial, viral, and fungal infections due to poor T-lymphocyte production and/or function, in addition to failure of B lymphocytes to generate functional antibodies. SCID is the extreme form of CID. Patients with this condition often present in the first year of life, with severe life-threatening infections, and consequently failure to thrive, requiring prompt intervention. SCID without treatment is usually fatal within the first year of life. 2 Both SCID and CID are genetically diverse syndromes, and over 50 molecular defects resulting in these syndromes have been described. 3 Approximately 30% of SCID patients have defects in V(D)J recombination (antigen receptor

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CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

Cited by 31 publications

References 44 publications

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID

SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID

Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

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