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NCKAP1L defects lead to primary immunodeficincy and lymphoproliferation within a Hemophagocytic Lymphohistiocytosis-like syndrome

ABSTRACT: The Nck-Associated Protein 1-Like NCKAP1L gene, alternatively called Hematopoietic protein 1 (HEM-1), encodes a hematopoietic-specific regulator of the actin cytoskeleton, part of the WAVE2 complex. NCKAP1L is involved in lymphocyte development, phagocytosis and neutrophils migration. Here we report the first cases of NCKAP1L-deficiency in man, as homozygous non-sense or splice variants, observed in 2 independent patients of Middle-Eastern origin of 1.5 months and 9 years of age respectively. We described a novel nosological entity, combining to various degrees, immune deficiency, lymphoproliferation within a highly inflammatory syndrome, reminiscent, yet distinct of HLH; due to recessive mutations in NCKAP1L.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood

SUBMITTER: Aurélie Hirschler

LAB HEAD: Carapito Christine

PROVIDER: PXD018042 | Pride | 2020-07-23

REPOSITORIES: Pride

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NCKAP1L defects lead to primary immunodeficincy and lymphoproliferation within a Hemophagocytic Lymphohistiocytosis-like syndrome

Project description:The Nck-Associated Protein 1-Like NCKAP1L gene, alternatively called Hematopoietic protein 1 (HEM-1), encodes a hematopoietic-specific regulator of the actin cytoskeleton, part of the WAVE2 complex. NCKAP1L is involved in lymphocyte development, phagocytosis and neutrophils migration. Here we report the first cases of NCKAP1L-deficiency in man, as homozygous non-sense or splice variants, observed in 2 independent patients of Middle-Eastern origin of 1.5 months and 9 years of age respectively. We described a novel nosological entity, combining to various degrees, immune deficiency, lymphoproliferation within a highly inflammatory syndrome, reminiscent, yet distinct of HLH; due to recessive mutations in NCKAP1L.

2020-07-31 | PXD016191 | Pride

Germline ERCC6L2 mutations lead to impaired erythropoiesis and reshaping of the bone marrow niche

Project description:Despite the inclusion of inherited myeloid malignancies as a separate entity in the WHO Classification, our understanding of the etiology of familial leukemia remains limited. ERCC6L2-deficiency is a rare, life-threatening inherited condition that gives rise to bone marrow failure (BMF), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) resulting from germline mutations in DNA repair factor ERCC6L2. Here we employ a lentiviral shRNA approach to functionally characterize the impact of ERCC6L2 loss on hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). By combining cell culture assays and transcriptomic analysis of knockdown and ERCC6L2-mutated patient cells, we find that ERCC6L2-deficiency reduces HSPC clonogenic potential and delays erythropoiesis, while in MSCs it induces a significant lineage skewing, with increased osteogenesis and suppressed adipogenesis. Altogether, we demonstrate that ERCC6L2-deficiency impacts both hematopoietic and stromal compartments, and that our ex vivo model recapitulates patient phenotypes, providing a robust system to study germline mutations in hematological malignancies.

2022-09-26 | GSE190542 | GEO

RNAseq on PBMC of two patients with a novel syndromic entity combining immunodeficiency, lymphoproliferation and HLH-like phenotypes, and three age and sex-matched controls for each patient.

Project description:The study describes two independent cases of NCKAP1L-deficiency, both carrying homozygous non-sense or splice variants in the NCKAP1L gene. The patients presented a phenotype of immunodeficiency, lymphoproliferation and hyperinflammation with features of Hemophagocytic Lymphohistiocytosis (HLH).

2020-03-03 | E-MTAB-8524 | biostudies-arrayexpress

Bone marrow Mac1 and Gr1 positive cells of CALR-deficient and wild-type mice

Project description:We analyzed the effect of Calr deficiency on Mac1 and Gr1 positive bone marrow cells using hematopoietic cell specific Calr knockout (Mx-cre;Calrf/-) mice and control (Mx-cre;Calr+/+) mice.

2020-07-31 | PXD014854 | JPOST Repository

Thymic epithelial cell alterations and defective thymopoiesis lead to central and peripheral tolerance perturbation in MHCII deficiency

Project description:Major Histocompatibility Complex (MHC) class II (MHCII) deficiency, also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. The contribution of thymic epithelial cell (TEC) defects to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC alterations in this disease. We observed an overall perturbation of thymic structure and function in both MHCII-/- mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, in MHCII-/- mice, impaired cross-talk and mTEC maturation resulted in altered promiscuous gene expression and leaky central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential effect of hematopoietic stem cell transplantation in MHCII deficiency.

2022-01-28 | GSE166463 | GEO

Genome-wide maps of HLH-1 binding in muscle-enriched embryos.

Project description:To investigate the structure of the bodywall muscle differentiation network, we sought to both identify what role HLH-1 binding has in this regulation. We mapped the relationship between the regulatory targets and HLH-1 binding, as measured by ChIP-seq in animals enriched for bodywall muscle tissue through RNAi feeding. While regulatory targets are enriched for HLH-1 binding, the majority of HLH-1 binding actually occurs away from genes that are affected by hlh-1 loss of function. Nevertheless, HLH-1 binding is associated with both the expected E-box and, near genes belonging to specific regulatory subgroups, novel motifs that may serve as binding sites for cooperative transcription factors. HLH-1 binding genome-wide in the early embryo of C. elegans

2012-06-21 | E-GEOD-28561 | biostudies-arrayexpress

Autosomal Recessive CD70 Deficiency

Project description:<p>We describe four patients from two unrelated families of different ethnicities who had primary immunodeficiency predominantly manifesting as susceptibility to EBV-related diseases. We performed whole exome sequencing (P1 and P2 from family 1) or whole genome sequencing (P4 and both parents from family 2) in those two families and identified homozygous frameshift or in-frame deletions in CD70 in these patients which abolished either CD70 surface expression or binding to its counter structure CD27. Sanger sequencing identified the same homozygous <i>CD70</i> mutation in P3, which is not included in the dbGaP submission. Autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of CD27 deficiency.</p>

| phs001245 | dbGaP

Differential Effects of JAK1 vs. JAK2 Inhibition in Mouse Models of Hemophagocytic Lymphohistiocytosis

Project description:Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in pre-clinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, the JAK2 inhibitor fedratinib and the JAK1/2 inhibitor ruxolitinib. All three drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFNg)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, where perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, while fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent pro-inflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology.

2024-03-05 | GSE230771 | GEO

Plasma exosomal proteomic pattern in Hemophagocyticlymphohistiocytosis of a twin boy

Project description:Background: Secondary HLH is closely related to EBV infection, protein changes in plasma exosomes may be related to the pathogenesis of HLH patient. In recent years quantitative proteomic has been used to clarify the relationship between basic medicine and clinical medicine. Methods: Exosomes were isolated from plasma samples of a HLH patient and his twin brother. Plasma samples were classified into three groups according to the clinical presentation, namely T1 (the acute HLH), T2 (during pharmacological treatments), Ctr (the healthy control). Herein, we used TMT-based LC-MS/MS platform to identified and characterized HLH signatures before and during pharmacological treatments. Results: Exosomes’ marker proteins- CD63, TSG101, HSP70 were identified by western blotting. Through GO analysis and KEGG analysis, we found that the signaling pathways and functions enriched by differentially expressed genes are very different. We focus on describing? the significantly up-regulated proteins-MSN, HSPA8, CD163, and the significantly down-regulated proteins- PLG, FGG, F2. The significant changes of these factors are related to the deterioration of the disease Conclusion: Our exploratory study shows that the clinical symptoms and pathophysiological changes of HLH driven by EBV might be reflected in patients’ plasma exosomes. Plasma exosome proteomics provides new highlightinsights for into exploring the diagnostic and therapeutic biomarkers of HLH.

2022-05-19 | PXD019088 | Pride

Transcription profiling of C. elegans wild type (N2) and hlh-30(tm1978) mutants

Project description:The hlh-30 gene encodes a C. elegans basic-helix-loop-helix (bHLH) transcription factor; We compared RNA from wild type worms and worms mutant for the hlh-30 gene to identify putative target genes of the HLH-30 transcription factor. Experiment Overall Design: Total RNA from three biological replicates were isolated from embryos, L1 larvae, and L2 larvae from both wild type and hlh-30(tm1978) mutant worms

2009-08-07 | E-GEOD-15762 | biostudies-arrayexpress

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