Somatic genetic rescue in Mendelian haematopoietic diseases

Revy, Patrick; Kannengiesser, Caroline; Fischer, Alain

doi:10.1038/s41576-019-0139-x

Cited by 87 publications

(79 citation statements)

References 178 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…S21T). The normal levels of IFN-γ production could not be attributed to cells with a revertant genotype, as reported in other T-cell primary immunodeficiency diseases (PIDs), because the IFN-γ + BCGspecific T-cell clones still carried the TBX21 indel variant (data not shown) (Davis et al, 2008;Revy et al, 2019). Thus, the prolonged immunity to BCG infection mediated by Vδ2 + γδ T and memory CD4 + T cells was divergently controlled by T-bet, as T-bet was required for the generation of long-term immunity due to Vδ2 + γδ T cells, but redundant for IFN-γ production by BCGspecific cognate TH1* cells.…”

Section: Redundant Role Of T-bet In Ifn-γ Production By Bcg-specific mentioning

confidence: 76%

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Yang

Mele²,

Worley

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryInborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2− γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ TH1* cells unable to compensate for this deficit.

show abstract

Section: Redundant Role Of T-bet In Ifn-γ Production By Bcg-specific mentioning

confidence: 76%

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Yang

Mele²,

Worley

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…14,15 This phenomenon may involve the correction of the mutation to the wild-type genotype or the occurrence of compensatory second-site mutations which offset the primary variant. 14,15 It has been described in diverse genetic disorders, including hematological diseases, such as Wiskott-Aldrich syndrome, Fanconi anemia and several immunodeficiencies. 14,15 In this patient, mosaicism involved the hematopoietic stem cell and mature blood cells, indicating genetic reversion in the hematopoietic system.…”

Section: Case Reportsmentioning

confidence: 99%

“…14,15 It has been described in diverse genetic disorders, including hematological diseases, such as Wiskott-Aldrich syndrome, Fanconi anemia and several immunodeficiencies. 14,15 In this patient, mosaicism involved the hematopoietic stem cell and mature blood cells, indicating genetic reversion in the hematopoietic system. In rescued cells, the constitutional RUNX1 mutation was reverted to the wild-type sequence.…”

Section: Case Reportsmentioning

confidence: 99%

“…In this regard, it is noteworthy to highlight the relatively high frequency of somatic rescue events in genome instability syndromes, such as Fanconi or Bloom syndromes. 15 More widespread use of high-throughput technologies might determine whether somatic rescue events occur more frequently than currently appreciated in FPD/AML, which might contribute to variability in phenotypic presentation.…”

Section: Case Reportsmentioning

confidence: 99%

See 1 more Smart Citation

First description of revertant mosaicism in familial platelet disorder with predisposition to acute myelogenous leukemia: correlation with the clinical phenotype

et al. 2020

View full text Add to dashboard Cite

“…It generates a rather diverse repertoire, since 1,000 distinct TCRB sequences were expressed by mature CD4 and CD8 T cells. These cells expanded too, since the patient’s T cell count was approximately half that of age-matched controls (Stephan et al, 1996; Revy et al, 2019). A similar schema can also account for partial correction of SCID-ADA (Hirschhorn et al, 1996).…”

Section: “Natural” Gene Therapy In Patients With Scidmentioning

confidence: 99%

Gene therapy for severe combined immunodeficiencies and beyond

Fischer

Hacein‐Bey‐Abina

2019

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott–Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.

show abstract

Somatic genetic rescue in Mendelian haematopoietic diseases

Cited by 87 publications

References 178 publications

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

First description of revertant mosaicism in familial platelet disorder with predisposition to acute myelogenous leukemia: correlation with the clinical phenotype

Gene therapy for severe combined immunodeficiencies and beyond

Contact Info

Product

Resources

About