We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor γ (IL2RG) gene to CD34 + BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) protooncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene, CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.
The recently described staphylococcal enterotoxins (SE) G and I were originally identified in two separate strains of Staphylococcus aureus. We have previously shown that the corresponding genes seg and sei are present in S. aureus in tandem orientation, on a 3.2-kb DNA fragment (Jarraud, J. et al. 1999. J. Clin. Microbiol. 37:2446–2449). Sequence analysis of seg-sei intergenic DNA and flanking regions revealed three enterotoxin-like open reading frames related to seg and sei, designated sek, sel, and sem, and two pseudogenes, ψ ent1 and ψ ent2. RT-PCR analysis showed that all these genes, including seg and sei, belong to an operon, designated the enterotoxin gene cluster (egc). Recombinant SEG, SEI, SEK, SEL, and SEM showed superantigen activity, each with a specific Vβ pattern. Distribution studies of genes encoding superantigens in clinical S. aureus isolates showed that most strains harbored such genes and in particular the enterotoxin gene cluster, whatever the disease they caused. Phylogenetic analysis of enterotoxin genes indicated that they all potentially derived from this cluster, identifying egc as a putative nursery of enterotoxin genes.
BACKGROUND-The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common γ chain.
BACKGROUND In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS All patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2 , MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.)
The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily char- IntroductionThe study of human T-cell primary immunodeficiencies has enabled the molecular characterization of many diseases caused by Mendelian inheritance of mutated genes [1][2][3][4] and has revealed the function of key molecules in T-cell biology. SCIDs are characterized by complete lack of T-cell development and, in some conditions, developmental blocks on other lymphoid lineages. 1,2 Several mechanisms can leads to faulty T-cell differentiation, such as the premature death of progenitor cells and impaired ␥c-dependent cytokine signaling, VDJ recombination, or pre-TCR signaling. 1 In other forms of T-cell primary immunodeficiency, TCR-mediated T-cell activation is defective but T-cell differentiation is partially or fully preserved. The latter variously include deficiencies in DOCK8, ZAP-70, ITK, ORA1, and STIM-1, all of which are involved in the signaling cascade downstream of the TCR, and in molecules involved in the NFB pathway, such as NEMO and IKB␣. 2,5,6 These conditions are collectively referred to as combined immunodeficiencies (CIDs), because the functional consequences also include defective Ab production.The molecular signatures of many more T-cell immunodeficiency phenotypes have yet to be identified. In the present study, we describe a new form of human CID observed in 4 patients from 2 families that is primarily characterized by a dramatically reduced pool of circulating naive T cells and impaired in vitro survival of the T-lymphocyte population. These patients were shown to carry homozygous mutations in the serine-threonine protein kinase 4 (STK4) gene, coding for the ubiquitously expressed mammalian sterile 20-like protein MST1. Methods Case reportsPatient F1P1 was born to a consanguineous family of Turkish origin (see Figure 1A). Since the age of 2, he had suffered from recurrent skin and lower respiratory tract infections caused by Streptococcus pneumoniae and Haemophilus influenzae, leading to bronchiectasis, recurrent perioral herpes simplex infections with positive anti-HSV1-2 IgG titer, Varicella zoster virus (VZV) infections, and extensive molluscum contagiosum. In addition, the patient had chronic EBV infection with persistent EBV viremia (53 000 copies/mL at the age of 11 years) and positive anti-EBNA-1 and anti-VCA IgG Ab. At the age of 5, patient F1P1 was successfully treated for EBV ϩ Hodgkin B-cell lymphoma. The patient (now 17) is receiving Ig replacement therapy and anti-infective prophylaxis with antibiotics and antivirals. Apart from lymphocytopenia, his blood counts are consistently normal. A CT scan of the thymus performed at 11 years of age was normal in appearance, structure, and size compared with agematched controls. He has no dysmorphic syndrome and his growth was within the normal range.Family F2 is consanguineous and of Turkish origin, with 3 children affected ( Figu...
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