SLAM Family Research Articles

Alteration of the germinal center checkpoint by the lupus associated NZM2410/NZW SLAM family genes in the Sle1b sub-locus (171.40)

Abstract C57BL/6 (B6) mice carrying the Sle1b sub-locus that harbors the lupus-associated NZM2410/NZW SLAM family genes produce anti-nuclear antibodies (ANA). However, the role and mechanisms of alteration in the germinal center (GC) checkpoint in the development of autoantibodies in these mice (named B6.Sle1b mice) is not clear. Here we show significantly higher spontaneously formed GC (Spt-GC) response in aged B6.Sle1b mice compared to B6 controls. The increased Spt-GC response in B6.Sle1b mice did not result from a generalized defect in the response of B cells expressing Sle1b as no difference was observed between two groups of mice in the anti-sheep red blood cell (sRBC) GC responses. We found a significant increase in CD4+CXCR5hiPD-1hi follicular helper T cells (TFH) within Spt-GC and anti-sRBC GCs in B6.Sle1b mice. The increase in Spt-GC and TFH cell responses in B6.Sle1b mice was not due to reduced CD4+CD25+Foxp3+ T effector (iTreg) and TFH regulatory (TFR) cells in GCs. Sle1b GCs compared to controls had significantly higher proliferating B cells. This elevated Spt-GC response in B6.Sle1b mice was associated with increased DNA and nucleosome-specific plasma cells (PCs), memory B cells and ANAs. These data indicate that the mechanisms that control the formation of Spt-GCs and generation of autoreactive B and TFH cells in GCs are altered by the NZM2410/NZW SLAM family genes located in Sle1b.

Characterization of Ly108 in the Thymus: Evidence for Distinct Properties of a Novel Form of Ly108

Ly108 (CD352) is a member of the signaling lymphocyte activation molecule (SLAM) family of receptors that signals through SLAM-associated protein (SAP), an SH2 domain protein that can function by the recruitment of Src family kinases or by competition with phosphatases. Ly108 is expressed on a variety of hematopoietic cells, with especially high levels on developing thymocytes. We find that Ly108 is constitutively tyrosine phosphorylated in murine thymi in a SAP- and Fyn kinase-dependent manner. Phosphorylation of Ly108 is rapidly lost after thymocyte disaggregation, suggesting dynamic contact-mediated regulation of Ly108. Similar to recent reports, we find at least three isoforms of Ly108 mRNA and protein in the thymus, which are differentially expressed in the thymi of C57BL/6 and 129S6 mice that express the lupus-resistant and lupus-prone haplotypes of Ly108, respectively. Notably, the recently described novel isoform Ly108-H1 is not expressed in mice having the lupus-prone haplotype of Ly108, but is expressed in C57BL/6 mice. We further provide evidence for differential phosphorylation of these isoforms; the novel Ly108-H1does not undergo tyrosine phosphorylation, suggesting that it functions as a decoy isoform that contributes to the reduced overall phosphorylation of Ly108 seen in C57BL/6 mice. Our study suggests that Ly108 is dynamically regulated in the thymus, shedding light on Ly108 isoform expression and phosphorylation.

Genome-Wide Association Study of Treatment Refractory Schizophrenia in Han Chinese

We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04×10−7) and rs11265461 (P = 1.94×10−7) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94×10−6) and rs230529 (P = 1.74×10−7) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05×10−5) and rs3827219 (P = 1.66×10−5) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87×10−5) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85×10−6). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.

To be or not to be a stem cell: dissection of cellular and molecular components of haematopoietic stem cell niches

Recent studies have identified multiple cell types that regulate haematopoietic stem cells (HSCs); however, proof that a specific cell type produces a specific factor important for HSC function and maintenance is largely lacking. Ding et al (2012) reported recently that conditional deletion of stem cell factor (SCF) in Leptin receptor ( Lepr ) expressing perivascular cells or endothelial and haematopoietic cells resulted in significant reductions in number but less profound reduction in function of HSCs. Although the long‐term fate of HSCs in these models is largely unexplored and an underlying mechanism for reduction in HSCs not yet reported, these findings further implicate the vascular niche in the functional maintenance of HSCs in vivo and also raise intriguing questions for future studies in this field.

A functional role for the histone demethylase UTX in normal and malignant hematopoietic cells

Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), an H3K27Me2/3 demethylase, has been implicated in development, self-renewal, and differentiation of various organs and embryonic stem cells through chromatin modifications and transcriptional regulation of important developmentally related genes, such as Hox genes. However, the function of UTX in hematopoiesis is not well understood. To study the role of UTX in the mammalian hematopoietic system, we used lentiviral short hairpin RNA constructs to knockdown UTX in the murine hematopoietic progenitor cell line EML, in primary murine bone marrow cells and in leukemic cell lines. We report that Utx is highly expressed in the hematopoietic compartment and that it plays an important role in cell proliferation and homeostasis of hematopoietic cells in vitro. Knockdown of UTX in EML and primary murine bone marrow cells impairs their colony-forming ability. Moreover, knockdown of UTX affects expression of key genes that regulate hematopoietic differentiation such as Mll1, Runx1, and Scl in primary murine bone marrow cells. And we further demonstrate that UTX directly associates with the promoters of the Mll1, Runx1, and Scl genes and modulate their transcription by controlling H3K27me3 marks on respective promoter regions. In addition, UTX depletion severely impaired proliferation of several human leukemia cell lines. Together, these data demonstrate a functional role for UTX in normal and malignant hematopoiesis.

Trogocytosis Is a Gateway to Characterize Functional Diversity in Melanoma-Specific CD8+ T Cell Clones

Trogocytosis, the transfer of membrane patches from target to immune effector cells, is a signature of tumor-T cell interaction. In this study, we used the trogocytosis phenomenon to study functional diversity within tumor-specific T cell clones with identical TCR specificity. MART-1(26-35)-specific CD8 T cell clones, which differed in their trogocytosis capacity (low [2D11], intermediate [2G1], high [2E2]), were generated from melanoma patients. Functional evaluation of the clones showed that the percentage of trogocytosis-capable T cells closely paralleled each clone's IFN-γ and TNF-α production, lysosome degranulation, and lysis of peptide-pulsed targets and unmodified melanoma. The highly cytotoxic 2E2 clone displayed the highest TCR peptide binding affinity, whereas the low-activity 2D11 clone showed TCR binding to peptide-MHC in a CD8-dependent manner. TCR analysis revealed Vβ16 for clones 2E2 and 2G1 and Vβ14 for 2D11. When peptide-affinity differences were bypassed by nonspecific TCR stimulation, clones 2E2 and 2D11 still manifested distinctive signaling patterns. The high-activity 2E2 clone displayed prolonged phosphorylation of ribosomal protein S6, an integrator of MAPK and AKT activation, whereas the low-activity 2D11 clone generated shorter and weaker phosphorylation. Screening the two clones with identical TCR Vβ by immunoreceptor array showed higher phosphorylation of NK, T, and B cell Ag (NTB-A), a SLAM family homophilic receptor, in clone 2E2 compared with 2G1. Specific blocking of NTB-A on APCs markedly reduced cytokine production by CD8 lymphocytes, pointing to a possible contribution of NTB-A costimulation to T cell functional diversity. This finding identifies NTB-A as a potential target for improving anti-cancer immunotherapy.

Evolving role of 2B4/CD244 in T and NK cell responses during virus infection

The signaling lymphocyte activation molecule (SLAM) family receptor, 2B4/CD244, was first implicated in anti-viral immunity by the discovery that mutations of the SLAM-associated protein, SAP/SH2D1A, impaired 2B4-dependent stimulation of T and natural killer (NK) cell anti-viral functions in X-linked lymphoproliferative syndrome patients with uncontrolled Epstein–Barr virus infections. Engagement of 2B4 has been variably shown to either activate or inhibit lymphocytes which express this receptor. While SAP expression is required for stimulatory functions of 2B4 on lymphocytes, it remains unclear whether inhibitory signals derived from 2B4 can predominate even in the presence of SAP. Regardless, mounting evidence suggests that 2B4 expression by NK and CD8 T cells is altered by virus infection in mice as well as in humans, and 2B4-mediated signaling may be an important determinant of effective immune control of chronic virus infections. In this review, recent findings regarding the expression and function of 2B4 as well as SAP on T and NK cells during virus infection is discussed, with a focus on the role of 2B4–CD48 interactions in crosstalk between innate and adaptive immunity.

A Two-Gene Signature, SKI and SLAMF1, Predicts Time-to-Treatment in Previously Untreated Patients with Chronic Lymphocytic Leukemia

We developed and validated a two-gene signature that predicts prognosis in previously-untreated chronic lymphocytic leukemia (CLL) patients. Using a 65 sample training set, from a cohort of 131 patients, we identified the best clinical models to predict time-to-treatment (TTT) and overall survival (OS). To identify individual genes or combinations in the training set with expression related to prognosis, we cross-validated univariate and multivariate models to predict TTT. We identified four gene sets (5, 6, 12, or 13 genes) to construct multivariate prognostic models. By optimizing each gene set on the training set, we constructed 11 models to predict the time from diagnosis to treatment. Each model also predicted OS and added value to the best clinical models. To determine which contributed the most value when added to clinical variables, we applied the Akaike Information Criterion. Two genes were consistently retained in the models with clinical variables: SKI (v-SKI avian sarcoma viral oncogene homolog) and SLAMF1 (signaling lymphocytic activation molecule family member 1; CD150). We optimized a two-gene model and validated it on an independent test set of 66 samples. This two-gene model predicted prognosis better on the test set than any of the known predictors, including ZAP70 and serum β2-microglobulin.

Effects of Low ADAMTS 13 Levels and the Role of Von Willebrand Factor in Cardiovascular Disease

Abstract 5320 Von Willebrand factor (vWF) is a large multimeric glycoprotein that plays an important role as a co-factor in platelet adhesion and aggregation and as the circulating carrier for factor VIII; increased vWF levels, and the persistence of unprocessed ultra-large vWF multimers (ULVWF) that are hyperactive to binding GPIb-IX-V complex with high-strength bonds, precipitate platelet clumping in arterioles and capillaries, causing platelet aggregation and thrombotic microangiopathy resulting in tissue ischemia with an increased risk of CAD and stroke. vWF is the major ligand binding the subunit of trombospondin, P-selectin, collagen and SLAM family (signaling lymphocytic activation molecule), mediates platelet translocation, tethering and rolling under high shear stress and adhesion. The activity of VWF is modulated by ADAMTS-13 a Zn2+/Ca2+ dependent metalloprotease that cleaves vWF to smaller and less active forms at the tyr842/met843 within the A2 domain, and cleaves the tyr 1605/met 1606; this mechanism reduces the molecular weight and platelet-tethering function of vWF to the sub endothelium at high shear stress. ADAMTS-13 levels also correlate positively with cholesterol, triglycerides and body mass index (BMI). In addition, we have observed a negative association with fibrinogen, C-reactive protein, and ion trasport K+dependent Na+/Ca2+ exchange (SLC24A3); the phosphorylation of tyrosine 1605 and threonine/serine kinase inhibitors have negative effects on integrin GPIIb-IIIa that showed decrease expression. In patients with a level of ADAMTS-13 below 38%, the presence of ultra large vWF multimers is high and the relative risk of ischemic heart disease was 18.2% (95% CI, 0.8 to 4.2), and the relative risk of stroke was 11.5 % (95% CI, 0.6 to 3.9). We investigated the relation between the low activity of ADAMTS-13 and AMI or stroke; we measured VWF and ADAMTS-13 antigen levels in 16 patients with AMI, in 10 patients with stroke, and in 16 control subjects. We demonstrated that vWF levels are significantly higher in patients with AMI or stroke, while a severe decrease of ADAMTS-13 activity augments the risk of cardiovascular disease, and cerebral ischemia; measurement of both VWF and ADAMTS-13 may provide a good indicator for the likelihood of AMI and stroke. Disclosures: No relevant conflicts of interest to declare.

Adherens junction protein nectin-4 is the epithelial receptor for measles virus

Measles (MV) is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths1,2. While it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to initially infect macrophages and dendritic cells of the airways using the signaling lymphocytic activation molecule (SLAM, CD150) as receptor3-6. These cells then cross the respiratory epithelium and ferry the infection to lymphatic organs where MV replicates vigorously7. How and where the virus crosses back into the airways has remained unknown. Based on functional analyses of surface proteins preferentially expressed on virus-permissive epithelial cell lines, we identified nectin-48 (poliovirus-receptor-like-4) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is down-regulated in infected epithelial cells, including those of macaque tracheas. While other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that MV targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer9-11, which has implications for ongoing MV-based clinical trials of oncolysis12.

Molecular Pathogenesis of EBV Susceptibility in XLP as Revealed by Analysis of Female Carriers with Heterozygous Expression of SAP

Author SummaryX-linked lymphoproliferative disease (XLP) is an immunodeficiency caused by mutations in the SH2D1A gene, which encodes a cytoplasmic component, SAP involved in a signalling pathway in certain populations of immune cells. The Achilles' heel in XLP is extreme sensitivity to Epstein-Barr virus (EBV) infection. Although EBV infection in normal individuals is generally innocuous, in XLP it can be fatal. Strikingly, individuals with XLP do not display this same vulnerability to other viruses, and here we investigate what immune defects underlie this specific susceptibility. We developed a system to examine the behaviour of immune cells that are identical with the exception of whether or not they have a functional SH2D1A gene. This approach uses human female carriers of XLP (one of their X chromosomes carries the mutation). Following the process of X-chromosome inactivation in female cells, which is random, individuals harbour T cells that express the normal SH2D1A gene as well as cells that express the mutated version. We found that SAP-deficient CD8+ T cells fail to be activated by antigen-presenting B cells, but are activated by other antigen-presenting cell types. Since EBV selectively infects B cells, the exquisite sensitivity in XLP to EBV infection results from the ability of the virus to sequester itself in B cells, which can only induce a cytotoxic T cell response in SAP-sufficient cells. Thus, the functional defect in SAP-deficient CD8+ T cells does not relate to a specific virus but rather to the nature of the target cell presenting viral epitopes.

English

Stem cells are known to have the ability to renew themselves and differentiate into a diverse range of specialized cell types. Currently, the differentiation potential of human peripheral blood mononucleated cells in suspension as stem cells is not well-understood. The aim of this study was to investigate the differentiation potential of suspension mononucleated cells from human peripheral blood to differentiate. The osteoblast and osteoclast differentiation potential of suspension peripheral blood mononucleated cells were examined by molecular, biochemical and cell morphology analyses. The expression of osteoblast marker (osteonectin, SPARC) and osteoclast marker (tartrate resistant acid phosphatase, TRAP) as well as high alkaline phosphate (ALP) and TRAP enzyme activity were observed at days 14 and 10 of osteoblast and osteoclast differentiation, respectively. Morphology analyses showed that mononucleated cells successfully differentiated into osteoblasts and osteoclasts. The existence of stem cells in mononucleated cells was evaluated by the expression of a stem cell factor (KIT) and a haematopoietic stem cell marker (signalling lymphocytic activation molecule family member 1, SLAMF1). This study has shown that these suspension mononucleated cells possess differentiation potential through in vitro study. Human peripheral blood suspension mononucleated cells that have multi-lineage differentiation potential may provide a new source of stem cells that may be used for bone regeneration and tissue engineering applications.

Alternative splicing and mRNA expression analysis of bovine SLAMF7 gene in healthy and mastitis mammary tissues

The signaling lymphocyte-activating molecule family 7 (SLAMF7) proteins serve as adhesion molecules on the surface of a variety of mature hematopoietic cells, and also partially control certain innate and adaptive immune responses. We characterized three novel bovine SLAMF7 splice variants, designated as SLAMF7-AS1, AS2, and AS3. All three novel SLAMF7 isoforms are derived from the complete transcripts (SLAMF7-complete) via alternative splicing (AS). The patterns of the three splice variants are exon skipping and alternative 5' splice sites. Bovine SLAMF7 transcripts are expressed in mammary tissue, as demonstrated by real-time PCR. The levels of the complete transcript expression in the normal mammary tissues were higher than that in Staphylococcus aureus (Staph. aureus)-induced mastitis mammary tissues. However, it was not significant for the mRNA expression level comparison between these two kinds of mammary. The SLAMF-AS2 isoforms are expressed the lowest levels among the three transcripts in both normal and infected mammary tissues. This study provides clues for a better understanding of bovine SLAMF7 gene function.

Susceptibility loci for the defective foreign protein‐induced tolerance in New Zealand Black mice: Implication of epistatic effects of Fcgr2b and Slam family genes

In contrast to normal mice, autoimmune-prone New Zealand Black (NZB) mice are defective in susceptibility to tolerance induced by deaggregated bovine γ globulin (DBGG). To examine whether this defect is related to the loss of self-tolerance in autoimmunity, susceptibility loci for this defect were examined by genome-wide analysis using the F(2) intercross of nonautoimmune C57BL/6 (B6) and NZB mice. One NZB locus on the telomeric chromosome 1, designated Dit (Defective immune tolerance)-1, showed a highly significant linkage. This locus overlapped with a locus containing susceptibility genes for autoimmune disease, namely Fcgr2b and Slam family genes. To investigate the involvement of these genes in the defective tolerance to DBGG, we took advantage of two lines of Fcgr2b-deficient B6 congenic mice: one carries autoimmune-type, and the other carries B6-type, Slam family genes. Defective tolerance was observed only in Fcgr2b-deficient mice with autoimmune-type Slam family genes, indicating that epistatic effects of both genes are involved. Thus, common genetic mechanisms may underlie the defect in foreign protein antigen-induced tolerance and the loss of self-tolerance in NZB mouse-related autoimmune diseases.

Cutting Edge: An NK Cell-Independent Role for Slamf4 in Controlling Humoral Autoimmunity

Several genes within a syntenic region of human and mouse chromosome 1 are associated with predisposition to systemic lupus erythematosus. Analyses of lupus-prone congenic mice have pointed to an important role for the signaling lymphocyte activation molecule family (slamf)6 surface receptor in lupus pathogenesis. In this article, we demonstrate that a second member of the Slamf gene family, Slamf4 (Cd244), contributes to lupus-related autoimmunity. B6.Slamf4(-/-) mice spontaneously develop activated CD4 T cells and B cells and increased numbers of T follicular helper cells and a proportion develop autoantibodies to nuclear Ags. B6.Slamf4(-/-) mice also exhibit markedly increased autoantibody production in the B6.C-H-2bm12/KhEg → B6 transfer model of lupus. Although slamf4 function is best characterized in NK cells, the enhanced humoral autoimmunity of B6.Slamf4(-/-) mice is NK cell independent, as judged by depletion studies. Taken together, our findings reveal that slamf4 has an NK cell-independent negative regulatory role in the pathogenesis of lupus a normally non-autoimmune prone genetic background.

All Hematopoietic Cells Develop from Hematopoietic Stem Cells through Flk2/Flt3-Positive Progenitor Cells

While it is clear that a single hematopoietic stem cell(HSC) is capable of giving rise to all other hematopoietic cell types, the differentiation paths beyond HSC remain controversial. Contradictory reports onthe lineage potential of progenitor populations have questioned their physiological contribution of progenitor populations to multilineage differentiation. Here, we established a lineage tracing mouse model that enabled direct assessment of differentiation pathways invivo. We provide definitive evidence that differentiation into all hematopoietic lineages, including megakaryocyte/erythroid cell types, involves Flk2-expressing non-self-renewing progenitors. A Flk2+ stage was used during steady-state hematopoiesis, after irradiation-induced stress and upon HSC transplantation. In contrast, HSC origin and maintenance do not include a Flk2+ stage. These data demonstrate that HSC specification and maintenance are Flk2 independent, and that hematopoietic lineage separation occurs downstream of Flk2 upregulation.

The SLAM family member CD48 ( Slamf2) protects lupus-prone mice from autoimmune nephritis

Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains ( i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 ( Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48 −/−). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48 −/−) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low-grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48 −/− animals, neither BALB.129CD48 −/− mice nor B6 × BALB/c F1.129CD48 −/− progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner.

Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies

Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies.

SLAM Family Receptors and SAP Adaptors in Immunity

The signaling lymphocyte activation molecule (SLAM)-associated protein, SAP, was first identified as the protein affected in most cases of X-linked lymphoproliferative (XLP) syndrome, a rare genetic disorder characterized by abnormal responses to Epstein-Barr virus infection, lymphoproliferative syndromes, and dysgammaglobulinemia. SAP consists almost entirely of a single SH2 protein domain that interacts with the cytoplasmic tail of SLAM and related receptors, including 2B4, Ly108, CD84, Ly9, and potentially CRACC. SLAM family members are now recognized as important immunomodulatory receptors with roles in cytotoxicity, humoral immunity, autoimmunity, cell survival, lymphocyte development, and cell adhesion. In this review, we cover recent findings on the roles of SLAM family receptors and the SAP family of adaptors, with a focus on their regulation of the pathways involved in the pathogenesis of XLP and other immune disorders.

Abstract 4299: CD150, A predictor for xenotransplantation of acute lymphoblastic leukemia to NOD/SCID mice

Abstract CD150 is a member of the SLAM family that recently has been reported to be differentially expressed among primitive progenitors in the bone marrow of adult mouse. It was utilized to purify hematopoietic stem cells using a simple combination of SLAM family members. To elucidate the presence of this family on acute lymphoblastic leukemia (ALL), we analyzed the expression of this family member on human B-ALL progenitor cells, as well as its relationship with the engraftment of leukemic blasts in serial xenotransplantation assay. Expression analysis was carried out by flow cytometry. We combined the expression pattern of human CD150, CD244 and CD48 with serial xenotransplantation of B-ALL progenitor cells to indicate their relationship. Our data showed that CD48 and CD244 were expressed on most B-ALL progenitor cells, and interestingly only blast cells with low percentage of CD150+ population were able to reconstitute leukemia into primary, secondary and tertiary NOD/SCID mice. In conclusion, SLAM family members are present on B-ALL progenitor cells and the engraftment potential of leukemic blasts is correlated negatively with the proportion of CD150+ cells, the percentage of which can serve as a useful predictor for graft success of B-ALL to immune deficient mice. The mechanism of CD150 as a predictor is under further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4299. doi:10.1158/1538-7445.AM2011-4299