Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Positive, NK Cell-Negative

Last update 08 May 2025

Basic Info

Synonyms

JAK3 Deficiency, SCID, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-NEGATIVE, SCID, T Cell-Negative, B Cell-Positive, NK Cell-Negative

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Introduction

An autosomal recessive severe combined immunodeficiency caused by mutation(s) in the JAK3 gene, encoding tyrosine-protein kinase JAK3. It is characterized by decreased concentrations of T-cells and NK-cells and normal concentrations of B-cells.

Clinical Trials associated with Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Positive, NK Cell-Negative

NCT04370795

/ Enrolling by invitationPhase 1/2IIT

Matched Related and Unrelated Donor Stem Cell Transplantation for Severe Combined Immune Deficiency (SCID): Busulfan-based Conditioning With h-ATG, Radiation, and Sirolimus

Background:
Severe combined immune deficiency (SCID) is a group of conditions where the immune system does not work properly. The only cure for most SCIDs is a stem cell transplant (getting cells from a donor). These transplants can have serious complications. Before the transplant, people often get high doses of drugs and radiation to prepare the body to accept the cells from the donor. Researchers want to see if low doses of drugs alone without radiation work just as well as low doses of drugs with radiation for SCID patients getting stem cell transplants.
Objective:
To test a set of drugs with or without radiation given before a stem cell transplant.
Eligibility:
People ages 3-40 who have SCID and who have a stem cell donor - either related or unrelated.
Design:
Participants will be admitted to the hospital 10 days before transplant. They will undergo:
medical history
medication review
physical exam
blood and urine tests (may include a 24-hour urine collection)
heart, lung, and breathing tests
imaging scans
bone marrow sample
nutrition assessment
dental exam
eye exam
meeting with a social worker.
Participants will get a plastic port called a central line. It is a hollow tube that is placed in the upper chest. It will be used to give medicines and take blood.
All participants will take chemotherapy drugs. Some will get radiation.
Participants will have a stem cell transplant. They will get the cells as an infusion through their central line. They will stay in the hospital for 30 days after transplant.
Participants must stay within 1 hour of NIH for 3 months after transplant. During this time, they will have follow-up visits at NIH at least once a week. Then they will have follow-up visits once or twice a year for 5-6 years.

Start Date07 May 2025

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

100 Clinical Results associated with Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Positive, NK Cell-Negative

100 Translational Medicine associated with Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Positive, NK Cell-Negative

0 Patents (Medical) associated with Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Positive, NK Cell-Negative

Literatures (Medical) associated with Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Positive, NK Cell-Negative

01 Apr 2025·Journal for ImmunoTherapy of Cancer

JAK3^A573VandJAK3^M511Imutations in peripheral T-cell lymphoma mediating resistance to anti-PD-1 therapy through the STAT3/PD-L1 pathway

Article

Author: Yang, Mengwei ; Tang, Le ; Zhang, Lei ; Han, Xiaohong ; Shi, Yuankai ; Lou, Ning ; Gao, Ruyun ; Yao, Jiarui ; Xie, Zucheng

BackgroundClinical evidence has established anti-PD-1 antibody as a transformative treatment modality for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL), yet reveals a therapeutic plateau with drug resistance observed in 60% of r/r PTCL. The biological determinants underlying this resistance—particularly the complex interplay between tumor-intrinsic characteristics (including tumor mutation burden and oncogenic mutations) and immune microenvironment features (notably PD-L1 expression)—remain insufficiently illustrated. Therefore, we systematically depicted the comprehensive mutation profile of r/r PTCL patients and correlated them with the efficacy and prognosis of anti-PD-1 therapy.MethodsHere, we enrolled a cohort of 109 patients with r/r PTCL and performed targeted next-generation sequencing of 440 cancer-associated genes. Clinical information was collected and correlated with genetic mutations. We constructedJAK3mutant models using Jurkat and BA/F3 cell lines. We performed single-cell transcriptomics, western blotting, and flow cytometry to elucidate the molecular mechanism. Additionally, we built aJAK3-mutant syngeneic mouse model to demonstrate in vivo antitumor efficacy of Tofacitinib and anti-PD-1 therapy.ResultsWe identified and validated that PD-L1 was a predictor for the efficacy of anti-PD-1 therapy in PTCL patients. The subset of PTCL patients (13.5%) characterized by enrichment of the APOBEC-related mutation signature had worse overall survival (p=0.031) compared with non-APOBEC-enriched samples.JAK3andEZH2mutations were associated with lower PD-L1 expression (p<0.05), andJAK3mutations were independently correlated with shorter progression-free survival (HR=6.07, p=0.0144). Among all types ofJAK3mutations, single-cell transcriptomics, western blotting, and flow cytometry revealed thatJAK3p.A573V and p.M511I mutations led to decreased PD-L1 expression in Jurkat and BA/F3 cell lines through inactivation of STAT3. Compared withJAK3wild-type syngeneic mouse models,JAK3p.A573V and p.M511I mutant mice were more sensitive to Tofacitinib but not anti-PD-1 antibody.ConclusionsIn conclusion, we found thatJAK3mutations, especiallyJAK3p.A573V andJAK3p.M511I mutations, lead to poor prognosis of anti-PD-1 therapy through the STAT3/PD-L1 pathway. Tofacitinib is more suitable than anti-PD-1 antibody forJAK3mutant PTCL patients.Trial registration numberNCT03502629.

13 Sep 2023·Human Mutation

Combination of Synonymous and Missense Mutations in JAK3 Gene Contributes to Severe Combined Immunodeficiency in One Child

Article

Author: Wang, Xingcui ; Zhang, Haozheng ; Zhang, Kaihui ; He, Qiuxia ; Tian, Rujin ; Lin, Guiyu ; Liu, Qinghua ; Gao, Min ; Bai, Lu ; Wang, Dong ; Abdalla, Mohnad ; Lv, Yuqiang ; Liu, Yi

Janus kinase 3 (JAK3, NP_000206.2) is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction JAK/STAT pathway. JAK3 gene variants can lead to autosomal recessive severe combined immunodeficiency (SCID), which is T-cell-negative, B-cell-positive, and NK-cell-negative (OMIM: 600802). We have detected one infant suffering from cytomegalovirus, fever, and impaired respiratory function with low lymphocytes and immunoglobulin. Two compound heterozygous variants, c.1914G>T (p.L638=) and c.1048C>T (p.R350W), were identified in the proband, each of which was inherited from one unaffected parent. Analysis of splicing was carried out by the Sanger sequencing and RT-PCR from peripheral blood and a minigene splicing assay which both showed a deletion of exon 14 (128 bp) resulting from the c.1914G>T variant at the mRNA level. Bioinformatic analysis for the reported c.1048C>T (p.R350W) variant suggests that the variant is pathogenic. Based on the clinical characteristics of the patient and the functional verification of the gene variants, our pediatricians finally have diagnosed the infant as SCID (OMIM: 600802). The study is the first study regarding a synonymous variant of JAK3 gene influencing alternative splicing. Our findings expand the mutation spectrum leading to JAK3 deficiency-related diseases and provide exact information for genetic counseling.

01 Jun 2022·Leukemia

JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia

Article

Author: Devidas, Meenakshi ; Wood, Brent ; Stevenson, Kristen E ; Hunger, Stephen P ; Teachey, David T ; Meijerink, Jules P ; Letai, Anthony ; Yamagata, Natsuko ; Burns, Melissa ; Landrigan, Jack ; Barthe, Anais ; Gutierrez, Alejandro ; Silverman, Lewis B ; Chonghaile, Triona Ni ; Loh, Mignon L ; Bodaar, Kimberly

Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon sequencing analysis of childhood T-ALL clinical specimens, we found that mitochondrial apoptosis resistance was most strongly associated with activating mutations of JAK3. Mutant JAK3 directly repressed apoptosis in leukemia cells, because its inhibition with mechanistically distinct pharmacologic inhibitors resulted in reversal of mitochondrial apoptotic blockade. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL.

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