Clinical Flow Cytometric Screening of SAP and XIAP Expression Accurately Identifies Patients with<i>SH2D1A</i>and<i>XIAP/BIRC4</i>Mutations

Gifford, Carrie; Weingartner, Elizabeth; Villanueva, Joyce; Johnson, Judith A.; Zhang, Kejian; Filipovich, Alexandra H.; Bleesing, Jack J.; Marsh, Rebecca

doi:10.1002/cytob.21166

Cited by 34 publications

(18 citation statements)

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“…This sequence contains a glycine residue at position 188, whose germline mutation marks a causative molecular aberration of the X‐linked lymphoproliferative syndrome type 2 (XLP‐2), which features low or instable expression of XIAP and premature apoptosis of lymphocytes in response to different stimuli (Rigaud et al , ). Two respective mutations of XIAP at G188 have been described, G188E and G188R, which diminish XIAP expression levels in patient B cells (Marsh et al , ; Gifford et al , ). Indeed, we found that both mutations abolish binding of XIAP to USP9X, and both XIAP mutants demonstrate reduced stability in mitosis (Figs D and EV1C).…”

Section: Resultsmentioning

confidence: 99%

USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

et al. 2016

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The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma.

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Section: Resultsmentioning

confidence: 99%

USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

et al. 2016

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“…Flow cytometry can detect functional defects in signaling pathways of MDP among patients with XIAP deficiency. 53,54 Detection of antibodies against enterocytes can be useful in the diagnosis of autoimmune enteropathy, particularly among patients with IPEX syndrome. 52 Additional tests for other rare genetic defects may also help in the detection of subgroups of earlyonset IBD, but are usually only available at specialized laboratories, often as part of research projects.…”

Section: Differences Between Early and Late Onset Ibdmentioning

confidence: 99%

Early onset inflammatory bowel disease: manifestations, genetics and diagnosis

Moazzami¹,

Moazzami²,

Rezaei³

2019

Turk J Pediatr

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Crohn's disease and ulcerative colitis are immunologically mediated chronic inflammatory conditions, collectively referred to as inflammatory bowel diseases (IBD). While most studies have described the condition in the adult population, recent evidences suggest that IBD in children may represent an etiologically distinct disease from the adult onset IBD. Since a significant proportion of patients diagnosed with IBD demonstrate their clinical manifestations during childhood, knowledge about the disease progression, severity and diagnosis in this particular patient population is crucial. Therefore, in the present study, the clinical manifestations, recent advancements in the genetics of early onset IBD and the clinical approach to diagnoses of IBD in children are described.

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“…This approach has been shown to provide good sensitivity and specificity compared with genetic mutation evaluation, and it is characterized by high negative predictive value. The lack of intracellular perforin expression in NK cells is characteristic of familial hemophagocytic lymphohistiocytosis type 2 [26,27].…”

Section: Sap Xiap and Perforin Expression In Hemophagocytic Lymphohmentioning

confidence: 99%

Flow Cytometry Applied to the Diagnosis of Primary Immunodeficiencies

Martínez-Gallo¹,

García-Prat²

2020

Innovations in Cell Research and Therapy

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Primary immunodeficiencies are the result of biological defects associated with functional immune abnormalities. It consists of a group of disorders showing a higher incidence and severity of infections, expression of immunological dysregulation such as inflammation and lymphoproliferation. The immunophenotyping and in vitro functional characterization of immunodeficient patients contribute, together with the clinical aspects, to define the underlying immune defect particularities. Flow cytometry applications in primary immunodeficiency assessment are multiple and include the study of a wide range of specific cell lymphocyte subpopulations. This chapter describes the main techniques used in the diagnosis of a wide variety of primary immunodeficiencies, in which intracellular proteins or activation markers involved in immunity are evaluated, as well as functional proliferation, cytokine production, phosphorylation of transcription factors, cytotoxic and degranulation capacity. Flow cytometry is a tool that allows rapid and accurate evaluation of multiple lymphocyte populations and immunological function, and this information is essential for the diagnosis and evaluation of patients with primary immunodeficiencies.

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Clinical Flow Cytometric Screening of SAP and XIAP Expression Accurately Identifies Patients withSH2D1AandXIAP/BIRC4Mutations

Cited by 34 publications

References 0 publications

USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

Early onset inflammatory bowel disease: manifestations, genetics and diagnosis

Flow Cytometry Applied to the Diagnosis of Primary Immunodeficiencies

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