Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1126/scitranslmed.3007280 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Pan-cancer analysis of Arp2/3 complex subunits: focusing on ARPC1A's role and validating the ARPC1A/c-Myc axis in non-small cell lung cancer.
Front Immunol
January 2025
Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Background: The Arp2/3 complex is a key regulator of tumor metastasis, and targeting its subunits offers potential for anti-metastatic therapy. However, the expression profiles, prognostic relevance, and diagnostic value of its subunits across cancers remain poorly understood. This study aims to investigate the clinical relevance of Arp2/3 complex subunits, particularly ARPC1A, in pan-cancer, and to further analyze the potential biological mechanisms of ARPC1A, as well as its association with immune infiltration and chemotherapy drug sensitivity.
View Article and Find Full Text PDFCommunity characteristics and relationship between gut microbiota and intratumoral microbiota in hepatocellular carcinoma.
Front Immunol
January 2025
The School of Clinical Medicine, Fujian Medical University, Fuzhou, China.
Background: The combination of local therapy with lenvatinib and programmed cell death protein-1 (PD-1) inhibitors represents an emerging treatment paradigm for unresectable hepatocellular carcinoma (uHCC). Our study sought to investigate the interrelationship between gut microbiota and intratumoral microbiota in the context of triple therapy, with a view to identifying potential biological markers.
Methods: The gut microbial community profiles of patients with primary untreated hepatocellular carcinoma (HCC) and those treated with local therapy combined with lenvatinib and PD-1 inhibitors were analyzed by 16S rRNA gene amplicon sequencing.
Development and validation of a glycolysis-associated gene signature for predicting the prognosis, immune landscape, and drug sensitivity in bladder cancer.
Front Immunol
January 2025
Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Background: Bladder cancer (BCa) is one of the most common malignancies worldwide, and its prognostication and treatment remains challenging. The fast growth of various cancer cells requires reprogramming of its energy metabolism using aerobic glycolysis as a major energy source. However, the prognostic and therapeutic value of glycolysis-related genes in BCa remains to be determined.
View Article and Find Full Text PDFPan-Cancer Analysis Identifies YKT6 as a Prognostic and Immunotherapy Biomarker, with an Emphasis on Cervical Cancer.
Onco Targets Ther
January 2025
Department of Gynecology, Sichuan Provincial Hospital of Traditional Chinese Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People's Republic of China.
Background: Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion is crucial for autophagy, making YKT6, a key modulator of cell membrane fusion, a potential target for cancer therapy. However, its oncogenic role across different cancers remains unclear. This study was to investigate the prognostic value and potential immunological functions of YKT6, including cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC).
View Article and Find Full Text PDFAn Open-Label Phase II Trial of Pembrolizumab, an Immune Checkpoint Inhibitor Alone or in Combination With Oral Azacitidine as Second-Line Therapy for Advanced Head and Neck Squamous Cell Cancers.
Health Sci Rep
January 2025
Medical Oncology Healthcare Global Bangalore India.
Background And Aims: Sensitivity to immune checkpoint inhibitor (ICI) therapy depends in part on the genetic and epigenetic makeup of cancer cells, and CD8 T-lymphocytes that mediate immune responses. Epigenetics are heritable reversible changes in gene expression that occur without any changes in the nuclear DNA sequence or DNA copy number.
Primary Objective: i.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!