CD19

Gene Summary

Gene:CD19; CD19 molecule
Aliases: B4, CVID3
Location:16p11.2
Summary:Lymphocytes proliferate and differentiate in response to various concentrations of different antigens. The ability of the B cell to respond in a specific, yet sensitive manner to the various antigens is achieved with the use of low-affinity antigen receptors. This gene encodes a cell surface molecule which assembles with the antigen receptor of B lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:B-lymphocyte antigen CD19
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD19 (cancer-related)

Nakatsuka SI, Yutani C, Kurashige M, et al.
An unusual case of Epstein-Barr virus-positive large B-cell lymphoma lacking various B-cell markers.
Diagn Pathol. 2017; 12(1):15 [PubMed] Free Access to Full Article Related Publications
BACKGROUD: Epstein-Barr virus (EBV) is associated with B-cell lymphoma in various conditions, such as immunodeficiency and chronic inflammation. We report an unusual case of EBV-positive diffuse large B-cell lymphoma (DLBCL) lacking the expression of many B-cell markers.
CASE PRESENTATION: An 83-year-old man presented with a submandibular tumor. Histology of a lymph node biopsy specimen revealed diffuse proliferation of centroblast- or immunoblast-like lymphoid cells with plasmacytic differentiation. Scattered Hodgkin/Reed-Sternberg-like cells were also visible. A routine immunohistochemistry antibody panel revealed that the tumor cells were negative for B-cell and T-cell markers (i.e., CD3, CD19, CD20, CD38, CD45RO, CD79a, CD138, and Pax-5), but were positive for CD30 and MUM-1, not defining the lineage of tumor cells. The final diagnosis of EBV-positive DLBCL was confirmed based on the expression of B-cell-specific transcription factors (Oct-2 and BOB.1), PCR-based identification of monoclonal rearrangement of the immunoglobulin genes, and the presence of EBV-encoded small RNAs in the tumor cells (identified using in situ hybridization).
CONCLUSION: The downregulation of broad band of B-cell markers in the present case with EBV-positive DLBCL posed a diagnostic dilemma, as the possible diagnoses included differentiation from anaplastic large cell lymphoma and CD20-negative B-cell lymphomas. Results of immunohistochemical panel including B-cell-specific transcription factors and gene rearrangement analyses critically support the correct diagnosis.

Yamamoto K, Kawamoto S, Mizutani Y, et al.
Mixed Phenotype Acute Leukemia with t(12;17)(p13;q21)/TAF15-ZNF384 and Other Chromosome Abnormalities.
Cytogenet Genome Res. 2016; 149(3):165-170 [PubMed] Related Publications
The t(12;17)(p13;q11∼21) translocation is a very rare but recurrent cytogenetic aberration observed predominantly in early pre-B acute lymphoblastic leukemia (ALL) with CD19+CD10-CD33+ phenotype. This translocation was shown to form a fusion gene between TAF15 at 17q12 and ZNF384 at 12p13. On the other hand, der(1;18)(q10;q10) has been detected as a rare unbalanced whole-arm translocation leading to trisomy 1q in myeloid malignancies. We describe here the first case of mixed phenotype acute leukemia (MPAL) with a t(12;17)(p13;q21)/TAF15-ZNF384, which also had der(1;18)(q10;q10) as an additional abnormality. A 74-year-old woman was diagnosed with MPAL, B/myeloid, because bone marrow blasts were positive for myeloperoxidase, CD19, and CD22. Chromosome analysis showed 46,XX, +1,der(1;18)(q10;q10),t(2;16)(q13;q13),t(12;17)(p13;q21). Expression of the TAF15-ZNF384 fusion transcript was confirmed: TAF15 exon 6 was fused in-frame to ZNF384 exon 3. This type of fusion gene has been reported in 1 acute myeloid leukemia case and 3 ALL cases. Thus, at present, it is difficult to find a specific association between the structure of the TAF15-ZNF384 fusion gene and the leukemia phenotype. The TAF15-ZNF384 fusion may occur in early common progenitor cells that could differentiate into both the myeloid and lymphoid lineages. Furthermore, der(1;18)(q10;q10) might play some role in the appearance of an additional myeloid phenotype.

Boice M, Salloum D, Mourcin F, et al.
Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.
Cell. 2016; 167(2):405-418.e13 [PubMed] Article available free on PMC after 06/10/2017 Related Publications
The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM((P37-V202))) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.

Li HF, Meng WT, Jia YQ, et al.
Development-associated immunophenotypes reveal the heterogeneous and individualized early responses of adult B-acute lymphoblastic leukemia.
Medicine (Baltimore). 2016; 95(34):e4128 [PubMed] Related Publications
B cell acute lymphoblastic leukemia (B-ALL) exhibits phenotypes reminiscent of normal stages of B-cell development. As demonstrated by flow cytometry, the immunophenotypes are able to determine the stages of B cell development. Multicolor flow cytometry (MFC) is more accurate at identifying cell populations. In this study, 9-color panels, including CD10, CD19, CD20, CD22, CD34, CD79a, CD179a, and IgM, which are sequentially expressed during B cell development, were designed to detect the leukemia cell subpopulations in adult B-ALL patients. In 23 patients at diagnosis, 192 heterogeneous subpopulations of leukemia cells were detected. Compared with their counterparts at diagnosis and after the 1st course of induction therapy, the responses of the subpopulations were also heterogeneous. In the CD10 population, the residual B cell subpopulations in the BCR/ABL patients were obviously reduced compared to those in the BCR/ABL patients. New subpopulations were detected in 22 of 23 patients and were primarily located in the CD34CD10 populations. Subpopulations of clonal evolution were heterogeneous after induction therapy. Our results suggest that the subpopulations in B-ALL patients should be dynamically monitored by development-associated immunophenotyping before, during, and after induction therapy and to predict the prognosis of the disease.

Venerito M, Helmke C, Jechorek D, et al.
Leukotriene receptor expression in esophageal squamous cell cancer and non-transformed esophageal epithelium: a matched case control study.
BMC Gastroenterol. 2016; 16(1):85 [PubMed] Article available free on PMC after 06/10/2017 Related Publications
BACKGROUND: Leukotriene B4 (LTB4R and LTB4R2) and cysteinyl leukotriene receptors (CYSLTR1 and CYSLTR2) contribute to malignant cell transformation. We aimed to investigate the expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 in esophageal squamous cell carcinoma and adjacent non-transformed squamous epithelium of the esophagus, as well as in control biopsy samples from esophageal squamous epithelium of patients with functional dyspepsia.
METHODS: Expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 was analyzed by immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in biopsy samples of 19 patients with esophageal squamous cell cancer and 9 sex- and age-matched patients with functional dyspepsia.
RESULTS: LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 were expressed in all biopsy samples. Major findings were: 1) protein levels of all leukotriene receptors were significantly increased in esophageal squamous cell cancer compared to control mucosa (p < 0.05); 2) CYSLTR1 and CYSLTR2 gene expression was decreased in cancer tissue compared to control at 0.26-fold and 0.23-fold respectively; 3) an up-regulation of LTB4R (mRNA and protein expression) and a down-regulation of CYSLTR2 (mRNA expression) in non-transformed epithelium of cancer patients compared to control (p < 0.05) was observed.
CONCLUSIONS: The expression of leukotriene receptors was deregulated in esophageal squamous cell cancer. Up-regulation of LTB4R and down-regulation of CYSLTR2 gene expression may occur already in normal squamous esophageal epithelium of patients with esophageal cancer suggesting a potential role of these receptors in early steps of esophageal carcinogenesis. Larger studies are warranted to confirm these observations.

Huang X, Zhou W, Zhang Y, Liu Y
High Expression of PTGR1 Promotes NSCLC Cell Growth via Positive Regulation of Cyclin-Dependent Protein Kinase Complex.
Biomed Res Int. 2016; 2016:5230642 [PubMed] Article available free on PMC after 06/10/2017 Related Publications
Lung cancer has been the most common cancer and the main cause of cancer-related deaths worldwide for several decades. PTGR1 (prostaglandin reductase 1), as a bifunctional enzyme, has been involved in the occurrence and progression of cancer. However, its impact on human lung cancer is rarely reported. In this study, we found that PTGR1 was overexpressed in lung cancer based on the analyses of Oncomine. Moreover, lentivirus-mediated shRNA knockdown of PTGR1 reduced cell viability in human lung carcinoma cells 95D and A549 by MTT and colony formation assay. PTGR1 depletion led to G2/M phase cell cycle arrest and increased the proportion of apoptotic cells in 95D cells by flow cytometry. Furthermore, silencing PTGR1 in 95D cells resulted in decreased levels of cyclin-dependent protein kinase complex (CDK1, CDK2, cyclin A2, and cyclin B1) by western blotting and then PTGR1 is positively correlated with cyclin-dependent protein by using the data mining of the Oncomine database. Therefore, our findings suggest that PTGR1 may play a role in lung carcinogenesis through regulating cell proliferation and is a potential new therapeutic strategy for lung cancer.

Nakazawa Y
Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies.
Rinsho Ketsueki. 2016; 57(6):701-8 [PubMed] Related Publications
Chimeric antigen receptor (CAR) is the generic name for synthetic T cell receptors redirected to tumor-associated antigens. Most CARs consist of an ectodomain (scFv or ligand), a hinge region, a transmembrane domain, and signaling endodomains derived from one or two co-stimulatory molecules (CD28, 4-1BB, etc) and from a CD3-ζ chain. CD19-targeted CAR T cell therapy has achieved major success in the treatment of B cell malignancies. CD19 CAR-T cells elicited complete remission in 70-90% of adult and pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). CD19 CAR T cell therapy from allogeneic donors including third party donors is a potential option for B-cell malignancies. CAR T cell therapies for myeloma, acute myeloid leukemia, and T-cell leukemia are still under development. Our group is currently preparing a phase I study of CD19 CAR T cell therapy in pediatric and young adult patients with ALL using a non-viral gene transfer method, the piggyBac-transposon system.

Xue L, Zhu Z, Wang Z, et al.
Knockdown of prostaglandin reductase 1 (PTGR1) suppresses prostate cancer cell proliferation by inducing cell cycle arrest and apoptosis.
Biosci Trends. 2016; 10(2):133-9 [PubMed] Related Publications
Chemoresistance is a serious problem for the treatment of androgen-independent prostate cancer (PC). The underlying molecular mechanisms by which androgen-independent PC cells acquire the capacity to proliferate remain largely unclear. The aim of this study was to investigate the biological role of prostaglandin reductase 1 (PTGR1) in prostate cancer. Data from the Oncomine database showed that PTGR1 is commonly upregulated in PC tissue in comparison to corresponding normal controls. Two PTGR1-specific short hairpin RNA (shRNA) sequences were used to block the expression of PTGR1 via a lentivirus-mediated system in the androgen-independent PC cell lines DU145 and PC 3. Functional analysis revealed that knockdown of PTGR1 significantly inhibited proliferation and colony formation by PC cells. The inhibition of cell proliferation was related to arrest of the cell cycle in the G0/G1 phase and increased apoptosis in response to PTGR1 knockdown as indicated by flow cytometry. PTGR1 silencing was found to mechanically enhance the expression of p21, caspase 3, and cleaved PARP and to decrease the level of cyclin D1. In conclusion, PTGR1 plays an essential role in PC cells and may be a potential therapeutic target for PC.

Maus MV, June CH
Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy.
Clin Cancer Res. 2016; 22(8):1875-84 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Chimeric antigen receptors (CAR) are engineered fusion proteins constructed from antigen recognition, signaling, and costimulatory domains that can be expressed in cytotoxic T cells with the purpose of reprograming the T cells to specifically target tumor cells. CAR T-cell therapy uses gene transfer technology to reprogram a patient's own T cells to stably express CARs, thereby combining the specificity of an antibody with the potent cytotoxic and memory functions of a T cell. In early-phase clinical trials, CAR T cells targeting CD19 have resulted in sustained complete responses within a population of otherwise refractory patients with B-cell malignancies and, more specifically, have shown complete response rates of approximately 90% in patients with relapsed or refractory acute lymphoblastic leukemia. Given this clinical efficacy, preclinical development of CAR T-cell therapy for a number of cancer indications has been actively investigated, and the future of the CAR T-cell field is extensive and dynamic. Several approaches to increase the feasibility and safety of CAR T cells are currently being explored, including investigation into the mechanisms regulating the persistence of CAR T cells. In addition, numerous early-phase clinical trials are now investigating CAR T-cell therapy beyond targeting CD19, especially in solid tumors. Trials investigating combinations of CAR T cells with immune checkpoint blockade therapies are now beginning and results are eagerly awaited. This review evaluates several of the ongoing and future directions of CAR T-cell therapy.

Guillory T, Li S, Bergsagel DJ, et al.
Hematogones With Lambda Light Chain Restriction in a 4-Year-Old Boy With Burkitt Lymphoma: A Potential Diagnostic Pitfall.
Lab Med. 2016; 47(2):163-70 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Hematogones are immature normal B cell precursors with a characteristic immunophenotype profile on flow cytometry that typically do not express surface immunoglobulin light chains. In this report, we describe a case in which the hematogones exhibit light chain restriction. Our patient was a 4-year-old boy with a complicated medical history involving treatment for a presumed bilateral Wilms tumor of the kidney that on later resection was diagnosed as Burkitt lymphoma. Flow cytometry analysis of his bone marrow revealed a small distinct population of cells expressing dim cluster of differentiation (CD)10, CD19, CD22, CD38, dim CD58, human leukocyte antigen-D related (HLA-DR), and dim CD45, which are characteristic of hematogones. These cells, however, demonstrated dim surface immunoglobulin lambda light-chain restriction. Molecular study results for immunoglobulin heavy and kappa light-chain gene rearrangements were negative. We present this case to raise awareness of the potential pitfalls of working up bone marrow for involvement by B cell lymphoproliferative disorder.

Di S, Li Z
Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects.
Sci China Life Sci. 2016; 59(4):360-9 [PubMed] Related Publications
Chimeric antigen receptors (CARs) are artificial recombinant receptors that generally combine the antigen-recognition domain of a monoclonal antibody with T cell activation domains. Recent years have seen great success in clinical trials employing CD19-specific CAR-T cell therapy for B cell leukemia. Nevertheless, solid tumors remain a major challenge for CAR-T cell therapy. This review summarizes the preclinical and clinical studies on the treatment of solid tumors with CAR-T cells. The major hurdles for the success of CAR-T and the novel strategies to address these hurdles have also been described and discussed.

Zhang Y, Jiang M, Li Q, et al.
Chromosome 15q25 (CHRNA3-CHRNB4) Variation Indirectly Impacts Lung Cancer Risk in Chinese Males.
PLoS One. 2016; 11(3):e0149946 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
INTRODUCTION: Recently, genome-wide association studies (GWAS) in Caucasian populations have identified an association between single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25, lung cancer risk and smoking behaviors. However, these SNPs are rare in Asians, and there is currently no consensus on whether SNPs in CHRNA5-A3-B4 have a direct or indirect carcinogenic effect through smoking behaviors on lung cancer risk. Though some studies confirmed rs6495308 polymorphisms to be associated with smoking behaviors and lung cancer, no research was conducted in China. Using a case-control study, we decided to investigate the associations between CHRNA3 rs6495308, CHRNB4 rs11072768, smoking behaviors and lung cancer risk, as well as explore whether the two SNPs have a direct or indirect carcinogenic effect on lung cancer.
METHODS: A total of 1025 males were interviewed using a structured questionnaire (204 male lung cancer patients and 821 healthy men) to acquire socio-demographic status and smoking behaviors. Venous blood samples were collected to measure rs6495308 and rs11072768 gene polymorphisms. All subjects were divided into 3 groups: non-smokers, light smokers (1-15 cigarettes per day) and heavy smokers (>15 cigarettes per day).
RESULTS: Compared to wild genotype, rs6495308 and rs11072768 variant genotypes reported smoking more cigarettes per day and a higher pack-years of smoking (P<0.05). More importantly, among smokers, both rs6495308 CT/TT and rs11072768 GT/GG had a higher risk of lung cancer compared to wild genotype without adjusting for potential confounding factors (OR = 1.36, 95%CI = 1.09-1.95; OR = 1.11, 95%CI = 1.07-1.58 respectively). Furthermore, heavy smokers with rs6495308 or rs11072768 variant genotypes have a positive interactive effect on lung cancer after adjustment for potential confounding factors (OR = 1.13, 95%CI = 1.01-3.09; OR = 1.09, 95%CI = 1.01-3.41 respectively). However, No significant associations were found between lung cancer risk and both rs6495308 and rs11072768 genotypes among non-smokers and smokers after adjusting for age, occupation, and education.
CONCLUSION: This study confirmed both rs6495308 and rs11072768 gene polymorphisms association with smoking behaviors and had an indirect link between gene polymorphisms and lung cancer risk.

Cornet E, Mossafa H, Courel K, et al.
Persistent polyclonal binucleated B-cell lymphocytosis and MECOM gene amplification.
BMC Res Notes. 2016; 9:138 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND: Persistent Polyclonal Binucleated B-cell Lymphocytosis (PPBL) is characterized by a chronic polyclonal B-cell lymphocytosis with binucleated lymphocytes and a polyclonal increase in serum immunoglobulin-M. Cytogenetic is characterized by the presence of a supernumerary isochromosome +i(3)(q10), premature chromosome condensation and chromosomal instability. Outcome of PPBL patients is mostly benign, but subsequent malignancies could occur. The aim of our study is to provide an update of clinical and cytogenetic characteristics of our large cohort of PPBL patients, to describe subsequent malignancies occurring during the follow-up, and to investigate the role of the long arm of chromosome 3 in PPBL.
RESULTS: We analyzed clinical, biological and cytogenetic characteristics (conventional cytogenetic analysis and fluorescent in situ hybridization) of 150 patients diagnosed with PPBL. We performed high-resolution SNP arrays in 10 PPBL patients, comparing CD19(+) versus CD19(-) lymphoid cells. We describe the cytogenetic characteristics in 150 PPBL patients consisting in the presence of supernumerary isochromosome +i(3)(q10) (59%) and chromosomal instability (55%). In CD19(+) B-cells, we observed recurrent copy number aberrations of 143 genes with 129 gains (90%) on 3q and a common minimal amplified genomic region in the MECOM gene. After a median follow-up of 60 months, we observed the occurrence of 12 subsequent malignancies (12%), 6 solid tumors and 6 Non-Hodgkin's Lymphomas, and 6 monoclonal gammopathies of undetermined significance (MGUS), requiring a long-term clinical follow-up.
CONCLUSIONS: Our clinical and cytogenetic observations lead us to hypothesize that isochromosome 3q, especially MECOM abnormality, could play a key role in PPBL.

Roth CG, Gillespie-Twardy A, Marks S, et al.
Flow Cytometric Evaluation of Double/Triple Hit Lymphoma.
Oncol Res. 2016; 23(3):137-46 [PubMed] Related Publications
"Double" or "triple" hit lymphomas (D/THL) with recurrent translocations involving MYC/8q24 and BCL2/18q21 and/or BCL6/3q27 are characterized by a poor prognosis, but their identification is hampered by the clinicopathologic overlap with other disease categories. Cases with circulating blastic-appearing cells may initially cause concern for lymphoblastic leukemia a diagnostic dilemma, which has not been well studied. There is only limited literature regarding the flow cytometric (FC) D/THL phenotype and its clinical correlates. The FC features of 20 D/THL (11 BCL2(+)/MYC(+), 5 BCL6(+)/MYC(+), 4 BCL2(+)/BCL6(+)/MYC(+)) were evaluated, compared to 20 B-lymphoblastic leukemias (B-LBL), and correlated with overall survival. Most (89%, 17/19) D/THL were CD10(+), 47% (9/19) lacked surface light chain, and a significant subset underexpressed CD45 (47%, 9/19), CD20 (42% 8/19), and/or CD19 (39%, 7/18), which did not vary by genetic subgroup. Compared to B-LBL, D/THL less frequently underexpressed CD45 (p = 0.0001) and CD20 (p = 0.0004). Lower levels of BCL2 expression were noted in the BCL6(+)/MYC(+) and BCL2(+)/BCL6(+)/MYC(+) subgroups versus BCL2(+)/MYC(+) cases (p = 0.0014). Of the flow cytometric parameters assessed, dim CD45 expression correlated with inferior survival (p = 0.01). Although there is some overlap with B-LBL, D/THL demonstrates a characteristic immunophenotype which may have prognostic significance and warrants further investigation.

Rombout A, Lust S, Offner F, et al.
Mimicking the tumour microenvironment of chronic lymphocytic leukaemia in vitro critically depends on the type of B-cell receptor stimulation.
Br J Cancer. 2016; 114(6):704-12 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
BACKGROUND: The B-cell receptor (BCR) has a key role in the cross-talk between chronic lymphocytic leukaemia (CLL) cells and the tissue microenvironment, which favours disease progression by promoting proliferation and drug resistance. In vitro studies on downstream signalling and functional effects of CLL BCR ligation often report contradictory results, in part owing to the lack of a standardised stimulation protocol. Our aim was to define a biologically relevant and robust in vitro stimulation method with regard to cellular phenotypic and transcriptional responses.
METHODS: We evaluated mRNA (FOS, MYC, LPL) and protein (CD54, CD19, CD62L, CD184) expression of genes modulated by BCR triggering in immunoglobulin heavy-chain variable region genes (IGHV)-mutated and -unmutated CLL cells, after stimulation using soluble or immobilised anti-IgM antibodies from different suppliers.
RESULTS: The effect of BCR stimulation on gene and protein expression was comparable in all CLL patients, irrespective of IGHV mutation status. However, immobilised anti-IgM stimulation elicited clear and robust changes in gene and protein expression, whereas the response to soluble anti-IgM was far less obvious.
CONCLUSIONS: These data indicate that the method of BCR stimulation is of major importance regarding responsiveness of CLL cells in the context of the tumour microenvironment, whereas genetic differences in the BCR pathway are less critical.

Rayes A, McMasters RL, O'Brien MM
Lineage Switch in MLL-Rearranged Infant Leukemia Following CD19-Directed Therapy.
Pediatr Blood Cancer. 2016; 63(6):1113-5 [PubMed] Related Publications
Rearrangements of the mixed lineage leukemia (MLL) gene occur frequently in infants with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Conversions of leukemia cell lineage are rare, but occur most commonly in the setting of MLL-rearrangement. Blinatumomab is a bidirectional antibody targeting CD19 with significant activity in relapsed B-precursor ALL. We report an infant with ALL with t(4;11)(q21;q23) refractory to cytotoxic chemotherapy who was treated with blinatumomab. Following rapid initial clearance of peripheral lymphoblasts, bone marrow evaluation demonstrated a leukemic lineage switch to CD19-negative monoblastic AML. Complete remission was achieved with myeloid-directed chemotherapy.

Feng Y, Tian J, Krylova I, et al.
Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model.
J Environ Sci (China). 2016; 39:218-27 [PubMed] Related Publications
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure in humans is associated with marked immune suppressions and increased incidence of lymphoblastic diseases. To elucidate mechanisms of impairments in humoral immune responses, we used a murine model. Following a 20-week administration of low doses of TCDD, we observed severely reduced antibody titers, dramatically decreased number of splenic Th1 and Th2 cells and an increase in CD19(+) B cells. Transcriptional profiling of CD19(+) B cells showed that markers of pre-B cells were significantly elevated, indicating delayed B cell maturation. These changes in B cells were accompanied by decreases of T helper cell numbers and reduced IgM and IgG titers. A transcriptome analysis of splenic B cells followed by Ingenuity Pathway Analysis (IPA) revealed a set of differentially expressed genes known to play roles in tumorigenesis, cell-proliferation and cell-migration. The most up-regulated transcript gene was Eph receptor A2 (EphA2), a known oncogene, and the most down-regulated transcript was ZBTB16 that codes for a negative transcriptional regulator important in epigenetic chromatin remodeling. IPA identified cAMP-responsive element modulator (CREM) and cAMP-responsive element binding protein 1 (CREB1) as top upstream regulators. Consistently, a MAPPER promoter database analysis showed that all top dysregulated genes had CREM and/or CREB1 binding sites in their promoter regions. In summary, our data showed that chronic TCDD exposure in mice caused suppressed humoral immunity accompanied with profound dysregulation of gene expression in splenic B-lymphocytes, likely through cAMP-dependent pathways. This dysregulation resulted in impairments in T-cell and B-cell differentiation and activation of the tumorigenic transcription program.

Yang S, Luo F, Wang J, et al.
Effect of prostaglandin reductase 1 (PTGR1) on gastric carcinoma using lentivirus-mediated system.
Int J Clin Exp Pathol. 2015; 8(11):14493-9 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Gastric carcinoma is a digestive related malignant tumor with poor diagnosis and prognosis for advanced patients. PTGR1 (prostaglandin reductase 1), as a potential cancer biomarker, has not been reported in gastric carcinoma occurrence. To investigate the role of PTGR1 on gastric carcinoma cells, human PTGR1 was efficiently silenced by lentivirus-mediated system in MGC-803 cells confirmed by quantitative real-time PCR (qRT-PCR) and western blot. Then cell proliferation, colony formation and cell cycle were determined after knockdown of PTGR1 by MTT assay, colony assay and flow cytometry, respectively and data suggested that PTGR1 down regulated MGC-803 cells significantly suppressed the proliferation and colony formation ability and induced cell cycle arrest in the G0/G1 phase compared to controls (P < 0.001). Further investigation demonstrated knockdown of PTGR1 influenced cell proliferation and cell cycle via activating p21 and p53 signaling pathway described by Western blot assay. Our findings indicate that PTGR1 may be an oncogene in human gastric carcinoma and identified as a diagnosis and prognosis target for gastric carcinoma.

Fraietta JA, Beckwith KA, Patel PR, et al.
Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.
Blood. 2016; 127(9):1117-27 [PubMed] Free Access to Full Article Related Publications
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749.

Srihari S, Kalimutho M, Lal S, et al.
Understanding the functional impact of copy number alterations in breast cancer using a network modeling approach.
Mol Biosyst. 2016; 12(3):963-72 [PubMed] Related Publications
UNLABELLED: Copy number alterations (CNAs) are thought to account for 85% of the variation in gene expression observed among breast tumours. The expression of cis-associated genes is impacted by CNAs occurring at proximal loci of these genes, whereas the expression of trans-associated genes is impacted by CNAs occurring at distal loci. While a majority of these CNA-driven genes responsible for breast tumourigenesis are cis-associated, trans-associated genes are thought to further abet the development of cancer and influence disease outcomes in patients. Here we present a network-based approach that integrates copy-number and expression profiles to identify putative cis- and trans-associated genes in breast cancer pathogenesis. We validate these cis- and trans-associated genes by employing them to subtype a large cohort of breast tumours obtained from the METABRIC consortium, and demonstrate that these genes accurately reconstruct the ten subtypes of breast cancer. We observe that individual breast cancer subtypes are driven by distinct sets of cis- and trans-associated genes. Among the cis-associated genes, we recover several known drivers of breast cancer (e.g. CCND1, ERRB2, MDM2 and ZNF703) and some novel putative drivers (e.g. BRF2 and SF3B3). siRNA-mediated knockdown of BRF2 across a panel of breast cancer cell lines showed significant reduction in cell viability for ER-/HER2+ (MDA-MB-453) cells, but not in normal (MCF10A) cells thereby indicating that BRF2 could be a viable therapeutic target for estrogen receptor-negative/HER2-enriched (ER-/HER2+) cancers. Among the trans-associated genes, we identify modules of immune response (CD2, CD19, CD38 and CD79B), mitotic/cell-cycle kinases (e.g. AURKB, MELK, PLK1 and TTK), and DNA-damage response genes (e.g. RFC4 and FEN1). siRNA-mediated knockdown of RFC4 significantly reduced cell proliferation in ER-negative normal breast and cancer lines, thereby indicating that RFC4 is essential for both normal and cancer cell survival but could be a useful biomarker for aggressive (ER-negative) breast tumours.
AVAILABILITY: under NetStrat.

Freedman A
Follicular lymphoma: 2015 update on diagnosis and management.
Am J Hematol. 2015; 90(12):1171-8 [PubMed] Related Publications
DISEASE OVERVIEW: Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma (FL) is characterized by diffuse lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, night sweats, and weight loss are uncommon.
DIAGNOSIS: Diagnosis is based on histology of preferably a biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes.
RISK STRATIFICATION: The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas > 4. The presence of 0, 1, 2, and ≥ 3 adverse factors defines low, intermediate, and high-risk disease. With the use of more modern therapies, outcomes have improved.
RISK-ADAPTED THERAPY: Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias, with no survival advantage for early treatment with either chemotherapy or rituximab alone. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab. Experimental therapies as well as stem cell transplantation (SCT) are considered for recurrent disease.

Rodgers DT, Mazagova M, Hampton EN, et al.
Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies.
Proc Natl Acad Sci U S A. 2016; 113(4):E459-68 [PubMed] Free Access to Full Article Related Publications
Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.

Alagpulinsa DA, Ayyadevara S, Yaccoby S, Shmookler Reis RJ
A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.
Mol Cancer Ther. 2016; 15(2):241-50 [PubMed] Free Access to Full Article Related Publications
PARP1/2 are required for single-strand break repair, and their inhibition causes DNA replication fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. The combined disruption of PARP and HR activities thus produces synthetic lethality. Multiple myeloma cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDK), upstream modulators of HR, are dysregulated in multiple myeloma. Here, we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes multiple myeloma cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased γH2AX foci. Dinaciclib treatment reduces expression of HR repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosome DSBs. Cotreatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of multiple myeloma cells, but not normal CD19(+) B cells, and slowed growth of multiple myeloma xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for multiple myeloma therapy. Mol Cancer Ther; 15(2); 241-50. ©2015 AACR.

Karlsson H, Svensson E, Gigg C, et al.
Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors.
PLoS One. 2015; 10(12):e0144787 [PubMed] Free Access to Full Article Related Publications
CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G) CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G) CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.

Nakamura Y, Tokita K, Nagasawa F, et al.
Chronic myelogenous leukemia in chronic phase transforming into acute leukemia under treatment with dasatinib 4 months after diagnosis.
Int J Hematol. 2016; 103(3):348-53 [PubMed] Related Publications
We report a 64-year-old woman morphologically diagnosed with chronic myelogenous leukemia in the chronic phase. Despite having achieved a complete hematological response following treatment with dasatinib, she developed lymphoblastic crisis 4 months later. Blastic cells were in a CD45-negative and SSC-low fraction, and positive for CD10, CD19, CD34, and HLA-DR expression and rearrangement in the immunoglobulin heavy chain gene. Chemotherapy using the HyperCVAD/MA regimen led to a complete cytogenetic response, and after cord blood transplantation, she obtained a complete molecular remission. However, the crisis recurred 6 months later. Another salvage therapy using L-AdVP regimen followed by nilotinib led to a complete molecular remission. Retrospective analyses using flow cytometry and polymerase chain reaction revealed a minimal blastic crisis clone present in the initial marrow in chronic phase. This case is informative as it suggests that sudden blastic crisis may occur from an undetectable blastic clone present at initial diagnosis and that leukemic stem cells may survive cytotoxic chemotherapy that eliminates most of the blastic cells.

Wotherspoon A, Attygalle A, Mendes LS
Bone marrow and splenic histology in hairy cell leukaemia.
Best Pract Res Clin Haematol. 2015; 28(4):200-7 [PubMed] Related Publications
Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over-estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma and hairy cell leukaemia variant. This can be done by assessment of the spleen but as this is now rarely performed in this disorder distinction is almost always possible by a combination of morphological and immunophenotypic studies on bone marrow trephine biopsy, which can be supplemented by assessment of BRAF-V600E mutation assessment in borderline cases.

Duque-Afonso J, Smith KS, Cleary ML
Conditional Expression of E2A-HLF Induces B-Cell Precursor Death and Myeloproliferative-Like Disease in Knock-In Mice.
PLoS One. 2015; 10(11):e0143216 [PubMed] Free Access to Full Article Related Publications
Chromosomal translocations are driver mutations of human cancers, particularly leukemias. They define disease subtypes and are used as prognostic markers, for minimal residual disease monitoring and therapeutic targets. Due to their low incidence, several translocations and their biological consequences remain poorly characterized. To address this, we engineered mouse strains that conditionally express E2A-HLF, a fusion oncogene from the translocation t(17;19) associated with 1% of pediatric B-cell precursor ALL. Conditional oncogene activation and expression were directed to the B-cell compartment by the Cre driver promoters CD19 or Mb1 (Igα, CD79a), or to the hematopoietic stem cell compartment by the Mx1 promoter. E2A-HLF expression in B-cell progenitors induced hyposplenia and lymphopenia, whereas expression in hematopoietic stem/progenitor cells was embryonic lethal. Increased cell death was detected in E2A-HLF expressing cells, suggesting the need for cooperating genetic events that suppress cell death for B-cell oncogenic transformation. E2A-HLF/Mb1.Cre aged mice developed a fatal myeloproliferative-like disorder with low frequency characterized by leukocytosis, anemia, hepatosplenomegaly and organ-infiltration by mature myelocytes. In conclusion, we have developed conditional E2A-HLF knock-in mice, which provide an experimental platform to study cooperating genetic events and further elucidate translational biology in cross-species comparative studies.

Vojkovics D, Kellermayer Z, Heidt D, et al.
Isolation and Characterization of a Murine Spontaneous High-Grade Follicular Lymphoma with Restricted In Vivo Spreading--a Model for Lymphatic Metastasis Via the Mesentery.
Pathol Oncol Res. 2016; 22(2):421-30 [PubMed] Related Publications
Spontaneous or induced malignant lymphomas in mice are valuable tools for studying human lymphoproliferative diseases, including the mechanism of migration between peripheral lymphoid organs and positioning within distinct tissue compartments. Here we report the isolation and characterization of a novel spontaneous lymphoma from BALB/c mice showing restricted tissue distribution and metastasis. The lymphoma cells display CD19, B220, MHC II, surface IgG2a/kappa chain with VH7183 rearrangement of the IgH gene, indicating their B-cell origin. Serial intraperitoneal injection of primary tumor into both BALB/c and RAG-1-deficient hosts led to the successful propagation of lymphoma. Despite the cytological characteristics of high-grade follicular B-cell lymphoma, the tumor cells (denoted as Bc-DLFL.1) showed significantly lesser spreading to extraabdominal locations upon intraperitoneal passage compared to splenic and mesenteric lymph node expansion. In mesenteric lymph nodes the high endothelial venules contained only few tumor cells, while the lymphatic vessels were almost completely filled with lymphoma cells. Similarly, the LYVE-1-positive lymphatic capillaries within the mesentery were packed with lymphoma cells. These findings suggest that Bc-DLFL.1 cells likely propagate primarily via the lymphatic circulation within the mesentery, therefore this tumor may offer an in vivo model to investigate the tumor cell migration via the lymphatic circulation from the peritoneal cavity.

Frey NV, Porter DL
CAR T-cells merge into the fast lane of cancer care.
Am J Hematol. 2016; 91(1):146-50 [PubMed] Related Publications
Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown remarkable activity against CD19+ malignancies including B cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL). Complete remission rates as high as 90% have been observed for patients with relapsed and refractory ALL and greater than 50% response rates have been seen in heavily pre-treated CLL and NHL. Excitingly, some remissions have been durable without any additional therapy, a finding which correlates with in-vivo T-cell persistence and B-cell aplasia. The major treatment related toxicities include B-cell aplasia, neurologic toxicities, and a potentially severe cytokine release syndrome. This review summarizes outcomes for patients treated with CD19-CAR T-cells while exploring the field's challenges and future directions.

Karyampudi L, Lamichhane P, Krempski J, et al.
PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-κB.
Cancer Res. 2016; 76(2):239-50 [PubMed] Free Access to Full Article Related Publications
The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-κB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer.

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