Gene Summary

Gene:CD19; CD19 molecule
Aliases: B4, CVID3
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:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:B-lymphocyte antigen CD19
Source:NCBIAccessed: 21 August, 2015


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 (1990-2015)
Graph generated 21 August 2015 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 21 August, 2015 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)

McClellan JS, Dove C, Gentles AJ, et al.
Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages.
Proc Natl Acad Sci U S A. 2015; 112(13):4074-9 [PubMed] Article available free on PMC after 30/09/2015 Related Publications
BCR-ABL1(+) precursor B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR-ABL1(+) B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR-ABL1(+) B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Finally, we determined that myeloid reprogramming may occur to some degree in human patients by identifying primary CD14(+) monocytes/macrophages in BCR-ABL1(+) B-ALL patient samples that possess the BCR-ABL1(+) translocation and clonally recombined VDJ regions.

Ghorashian S, Pule M, Amrolia P
CD19 chimeric antigen receptor T cell therapy for haematological malignancies.
Br J Haematol. 2015; 169(4):463-78 [PubMed] Related Publications
T cells can be redirected to recognize tumour antigens by genetic modification to express a chimeric antigen receptor (CAR). These consist of antibody-derived antigen-binding regions linked to T cell signalling elements. CD19 is an ideal target because it is expressed on most B cell malignancies as well as normal B cells but not on other cell types, restricting any 'on target, off tumour' toxicity to B cell depletion. Recent clinical studies involving CD19 CAR-directed T cells have shown unprecedented responses in a range of B cell malignancies, even in patients with chemorefractory relapse. Durable responses have been achieved, although the persistence of modified T cells may be limited. This therapy is not without toxicity, however. Cytokine release syndrome and neurotoxicity appear to be frequent but are treatable and reversible. CAR T cell therapy holds the promise of a tailored cellular therapy, which can form memory and be adapted to the tumour microenvironment. This review will provide a perspective on the currently available data, as well as on future developments in the field.

Othman MA, Grygalewicz B, Pienkowska-Grela B, et al.
Novel Cryptic Rearrangements in Adult B-Cell Precursor Acute Lymphoblastic Leukemia Involving the MLL Gene.
J Histochem Cytochem. 2015; 63(5):384-90 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
MLL (mixed-lineage-leukemia) gene rearrangements are typical for acute leukemia and are associated with an aggressive course of disease, with a worse outcome than comparable case, and thus require intensified treatment. Here we describe a 69-year-old female with adult B cell precursor acute lymphoblastic leukemia (BCP-ALL) with hyperleukocytosis and immunophenotype CD10- and CD19+ with cryptic MLL rearrangements. G-banding at the time of diagnosis showed a normal karyotype: 46,XX. Molecular cytogenetics using multitude multicolor banding (mMCB) revealed a complex rearrangement of the two copies of chromosome 11. However, a locus-specific probe additionally identified that the MLL gene at 11q23.3 was disrupted, and that the 5' region was inserted into the chromosomal sub-band 4q21; thus the aberration involved three chromosomes and five break events. Unfortunately, the patient died six months after the initial diagnosis from serious infections and severe complications. Overall, the present findings confirm that, by far not all MLL aberrations are seen by routine chromosome banding techniques and that fluorescence in situ hybridization (FISH) should be regarded as standard tool to access MLL rearrangements in patients with BCP-ALL.

Bouhassira DC, Thompson JJ, Davila ML
Using gene therapy to manipulate the immune system in the fight against B-cell leukemias.
Expert Opin Biol Ther. 2015; 15(3):403-16 [PubMed] Related Publications
INTRODUCTION: Over 20 years ago, chimeric antigen receptors (CARs) were created to endow T cells with new antigen-specificity and create a therapy that could eradicate cancer and provide life-long protection against recurrence. Steady progress has led to significant improvements with CAR design and CAR T-cell production, allowing evaluation of CAR T cells in patients. The initial trials have targeted CD19, which is expressed on normal and malignant B cells.
AREAS COVERED: We review data from trials for patients with chronic lymphocytic leukemia (CLL) and B-cell acute lymphoblastic leukemia (B-ALL). In addition, we discuss the on-target toxicities, B-cell aplasia and cytokine release syndrome (CRS), which is uniquely associated with T-cell immunotherapies.
EXPERT OPINION: We compare the results when targeting the same antigen in CLL or B-ALL and speculate on reasons for outcome differences and future directions to enhance outcomes. Furthermore, the dramatic results targeting B-ALL require further analysis in Phase II trials, and we discuss important components of these future trials. We also suggest a management scheme for CRS. The next several years will be critical and may lead to the first clinical indication of a gene-engineered cell therapy for cancer.

Balatti V, Rizzotto L, Miller C, et al.
TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia.
Proc Natl Acad Sci U S A. 2015; 112(7):2169-74 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression. We demonstrated that miR-3676 targets three consecutive 28-bp repeats within 3'UTR of TCL1 and showed that miR-3676 is a powerful inhibitor of TCL1. We further showed that miR-3676 expression is significantly down-regulated in four groups of CLL carrying the 11q deletions, 13q deletions, 17p deletions, or a normal karyotype compared with normal CD19(+) cord blood and peripheral blood B cells. In addition, the sequencing of 539 CLL samples revealed five germ-line mutations in six samples (1%) in miR-3676. Two of these mutations were loss-of-function mutations. Because miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 (Tp53), and is codeleted with Tp53, we propose that loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression.

Uckun FM, Myers DE, Qazi S, et al.
Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia.
J Clin Invest. 2015; 125(3):1006-18 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Patients with B cell precursor acute lymphoblastic leukemia (BPL) respond well to chemotherapy at initial diagnosis; however, therapeutic options are limited for individuals with BPL who relapse. Almost all BPL cells express CD19, and we recently cloned the gene encoding a natural ligand of the human CD19 receptor (CD19L). We hypothesized that fusion of CD19L to the soluble extracellular domain of proapoptotic TNF-related apoptosis-inducing ligand (sTRAIL) would markedly enhance the potency of sTRAIL and specifically induce BPL cell apoptosis due to membrane anchoring of sTRAIL and simultaneous activation of the CD19 and TRAIL receptor (TRAIL-R) apoptosis signaling pathways. Here, we demonstrate that recombinant human CD19L-sTRAIL was substantially more potent than sTRAIL and induced apoptosis in primary leukemia cells taken directly from BPL patients. CD19L-sTRAIL effectively targeted and eliminated in vivo clonogenic BPL xenograft cells, even at femtomolar-picomolar concentrations. In mice, CD19L-sTRAIL exhibited a more favorable pharmacokinetic (PK) profile than sTRAIL and was nontoxic at doses ranging from 32 fmol/kg to 3.2 pmol/kg. CD19L-sTRAIL showed potent in vivo antileukemic activity in NOD/SCID mouse xenograft models of relapsed and chemotherapy-resistant BPL at nontoxic fmol/kg dose levels. Together, these results suggest that recombinant human CD19L-sTRAIL has clinical potential as a biotherapeutic agent against BPL.

Booth L, Roberts JL, Cash DR, et al.
GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.
J Cell Physiol. 2015; 230(7):1661-76 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The chaperone GRP78/Dna K is conserved throughout evolution down to prokaryotes. The GRP78 inhibitor OSU-03012 (AR-12) interacted with sildenafil (Viagra) or tadalafil (Cialis) to rapidly reduce GRP78 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes. Similar data with the drug combination were obtained for: HSP70, HSP90, GRP94, GRP58, HSP27, HSP40 and HSP60. OSU-03012/sildenafil treatment killed brain cancer stem cells and decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola/Marburg/Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Chikungunya, Mumps, Measles, Rubella, RSV, CMV, and Influenza viruses. OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli and clinical isolate multi-drug resistant N. gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Rec A expression. The PDE5 inhibitors sildenafil or tadalafil enhanced OSU-03012 killing in N. gonorrhoeae and MRSE and low marginally toxic doses of OSU-03012 could restore bacterial sensitivity in N. gonorrhoeae to multiple antibiotics. Thus, Dna K and bacterial phosphodiesterases are novel antibiotic targets, and inhibition of GRP78 is of therapeutic utility for cancer and also for bacterial and viral infections.

Aoki Y, Watanabe T, Saito Y, et al.
Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.
Blood. 2015; 125(6):967-80 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

Gill S, June CH
Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies.
Immunol Rev. 2015; 263(1):68-89 [PubMed] Related Publications
On July 1, 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to CTL019, the anti-CD19 chimeric antigen receptor T-cell therapy developed at the University of Pennsylvania. This is the first personalized cellular therapy for cancer to be so designated and occurred 25 years after the first publication describing genetic redirection of T cells to a surface antigen of choice. The peer-reviewed literature currently contains the outcomes of more than 100 patients treated on clinical trials of anti-CD19 redirected T cells, and preliminary results on many more patients have been presented. At last count almost 30 clinical trials targeting CD19 were actively recruiting patients in North America, Europe, and Asia. Patients with high-risk B-cell malignancies therefore represent the first beneficiaries of an exciting and potent new treatment modality that harnesses the power of the immune system as never before. A handful of trials are targeting non-CD19 hematological and solid malignancies and represent the vanguard of enormous preclinical efforts to develop CAR T-cell therapy beyond B-cell malignancies. In this review, we explain the concept of chimeric antigen receptor gene-modified T cells, describe the extant results in hematologic malignancies, and share our outlook on where this modality is likely to head in the near future.

Iioka F, Akasaka T, Hayashida M, et al.
B-cell prolymphocytic leukemia carrying t(8;14)(q24;q32), associated with both autoimmune hemolytic anemia and pure red cell aplasia.
J Clin Exp Hematop. 2014; 54(3):219-24 [PubMed] Related Publications
An 80-year-old man was referred to our department because of lymphocytosis. His white cell count was 17.1 × 10(3)/μL, with 64% prolymphocytes. He did not exhibit splenomegaly or lymphadenopathy. Prolymphocytes were CD5(+), CD10(-), CD19(+), CD20(+), CD21(+weak), CD22(+), CD23(-), and HLA-DR(+), and expressed μδ/λ cell-surface immunoglobulins. G-banding and fluorescence in situ hybridization using c-MYC and immunoglobulin heavy-chain (IgH) gene probe revealed that leukemia cells carried the t(8;14)(q24;q32)/c-MYC-IgH fusion gene, and breakage and reunion occurred within the non-coding region of c-MYC exon 1 as well as the α switch region of IgH. Nine months after the initial presentation, the patient's hemoglobin level fell to 5.7 g/dL. Coombs' test was positive and marked hypoplasia of erythroid precursors was detected in his bone marrow. The patient was treated with prednisolone followed by 4 weekly doses of rituximab, which led to resolution of the anemia and complete response of the underlying leukemia. The role of t(8;14)(q24;q32)/c-MYC-IgH in the pathogenesis of B-cell prolymphocytic leukemia (B-PLL) may not be identical to that in aggressive lymphoid neoplasms, and, in the present case, autoantibodies targeting both mature red cells and erythroid precursors may have been concurrently produced in the setting of B-PLL.

Jahn L, Hombrink P, Hassan C, et al.
Therapeutic targeting of the BCR-associated protein CD79b in a TCR-based approach is hampered by aberrant expression of CD79b.
Blood. 2015; 125(6):949-58 [PubMed] Related Publications
Immunotherapy of B-cell malignancies using CD19-targeted chimeric antigen receptor-transduced T cells or CD20-targeted therapeutic monoclonal antibodies has shown clinical efficacy. However, refractory disease and the emergence of antigen-loss tumor escape variants after treatment demonstrate the need to target additional antigens. Here we aimed to target the B-cell receptor-associated protein CD79b by a T-cell receptor (TCR)-based approach. Because thymic selection depletes high-avidity T cells recognizing CD79b-derived peptides presented in self-HLA molecules, we aimed to isolate T cells recognizing these peptides presented in allogeneic HLA. Peptide-HLA tetramers composed of CD79b peptides bound to either HLA-A2 or HLA-B7 were used to isolate T-cell clones from HLA-A*0201 and B*0702-negative individuals. For 3 distinct T-cell clones, CD79b specificity was confirmed through CD79b gene transduction and CD79b-specific shRNA knockdown. The CD79b-specific T-cell clones were highly reactive against CD79b-expressing primary B-cell malignancies, whereas no recognition of nonhematopoietic cells was observed. Although lacking CD79b-cell surface expression, intermediate reactivity toward monocytes, hematopoietic progenitor cells, and T-cells was observed. Quantitative reverse transcriptase polymerase chain reaction revealed low CD79b gene expression in these cell types. Therefore, aberrant gene expression must be taken into consideration when selecting common, apparently lineage-specific self-antigens as targets for TCR-based immunotherapies.

Tseng TS, Park JY, Zabaleta J, et al.
Role of nicotine dependence on the relationship between variants in the nicotinic receptor genes and risk of lung adenocarcinoma.
PLoS One. 2014; 9(9):e107268 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four 'control' genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10(-10) and 1.1×10(-10), respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.

Bethge N, Honne H, Andresen K, et al.
A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma.
PLoS One. 2014; 9(9):e104249 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB) and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12), which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL). The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively). BMPER (58%), DUSP4 (32%) and BMP7 (22%), were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils) as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma.

Lucas CM, Harris RJ, Giannoudis A, et al.
Low leukotriene B4 receptor 1 leads to ALOX5 downregulation at diagnosis of chronic myeloid leukemia.
Haematologica. 2014; 99(11):1710-5 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
ALOX5 is implicated in chronic myeloid leukemia development in mouse leukemic stem cells, but its importance in human chronic myeloid leukemia is unknown. Functional ALOX5 was assessed using an LTB4 ELISA and ALOX5, and LTB4R1 mRNA expression was determined via a TaqMan gene expression assay. LTB4R1 and 5-LOX protein levels were assessed by cell surface flow cytometry analysis. At diagnosis ALOX5 was below normal in both blood and CD34(+) stem cells in all patients. On treatment initiation, ALOX5 levels increased in all patients except those who were destined to progress subsequently to blast crisis. LTB4 levels were increased despite low ALOX5 expression, suggesting that the arachidonic acid pathway is functioning normally up to the point of LTB4 production. However, the LTB4 receptor (BLT1) protein in newly diagnosed patients was significantly lower than after a period of treatment (P<0.0001). The low level of LTB4R1 at diagnosis explains the downregulation of ALOX5. In the absence of LTB4R1, the arachidonic acid pathway intermediates (5-HEPTE and LTA4) negatively regulate ALOX5. ALOX5 regulation is aberrant in chronic myeloid leukemia patients and may not be important for the development of the disease. Our data suggest caution when extrapolating mouse model data into human chronic myeloid leukemia.

Guerrero AD, Moyes JS, Cooper LJ
The human application of gene therapy to re-program T-cell specificity using chimeric antigen receptors.
Chin J Cancer. 2014; 33(9):421-33 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors (TCRs) or chimeric antigen receptors (CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin's lymphoma.

Saito S, Nakazawa Y, Sueki A, et al.
Anti-leukemic potency of piggyBac-mediated CD19-specific T cells against refractory Philadelphia chromosome-positive acute lymphoblastic leukemia.
Cytotherapy. 2014; 16(9):1257-69 [PubMed] Related Publications
BACKGROUND AIMS: To develop a treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) resistant to tyrosine kinase inhibitors (TKIs), we evaluated the anti-leukemic activity of T cells non-virally engineered to express a CD19-specific chimeric antigen receptor (CAR).
METHODS: A CD19.CAR gene was delivered into mononuclear cells from 10 mL of blood of healthy donors through the use of piggyBac-transposons and the 4-D Nucleofector System. Nucleofected cells were stimulated with CD3/CD28 antibodies, magnetically selected for the CD19.CAR, and cultured in interleukin-15-containing serum-free medium with autologous feeder cells for 21 days. To evaluate their cytotoxic potency, we co-cultured CAR T cells with seven Ph(+)ALL cell lines including three TKI-resistant (T315I-mutated) lines at an effector-to-target ratio of 1:5 or lower without cytokines.
RESULTS: We obtained ∼1.3 × 10(8) CAR T cells (CD4(+), 25.4%; CD8(+), 71.3%), co-expressing CD45RA and CCR7 up to ∼80%. After 7-day co-culture, CAR T cells eradicated all tumor cells at the 1:5 and 1:10 ratios and substantially reduced tumor cell numbers at the 1:50 ratio. Kinetic analysis revealed up to 37-fold proliferation of CAR T cells during a 20-day culture period in the presence of tumor cells. On exposure to tumor cells, CAR T cells transiently and reproducibly upregulated the expression of transgene as well as tumor necrosis factor-related apoptosis-inducing ligand and interleukin-2.
CONCLUSIONS: We generated a clinically relevant number of CAR T cells from 10 mL of blood through the use of piggyBac-transposons, a 4D-Nulcleofector, and serum/xeno/tumor cell/virus-free culture system. CAR T cells exhibited marked cytotoxicity against Ph(+)ALL regardless of T315I mutation. PiggyBac-mediated CD19-specific T-cell therapy may provide an effective, inexpensive and safe option for drug-resistant Ph(+)ALL.

Liu Z, Xu J, He J, et al.
A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance.
Blood. 2014; 124(13):2061-71 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Hedgehog (Hh) signaling plays an important role in the oncogenesis of B-cell malignancies such as multiple myeloma (MM). However, the source of Hh ligand sonic hedgehog (SHH) and its target cells remains controversial. Previous studies showed that stromally induced Hh signaling is essential for the tumor cells and that CD19(+)CD138(-) MM stem cells are the target cells of Hh signaling. Here we demonstrate that SHH was mainly secreted by human myeloma cells but not by stromal cells in MM bone marrow. Autocrine SHH enhanced CD138(+) myeloma cell proliferation and protected myeloma cells from spontaneous and stress-induced apoptosis. More importantly, autocrine SHH protected myeloma cells against chemotherapy-induced apoptosis in vitro and in vivo. Combinational treatment with chemotherapy and SHH-neutralizing antibody displayed synergistic antimyeloma effects. Mechanistic studies showed that SHH signaling activated the SHH/GLI1/BCL-2 axis, leading to the inhibition of myeloma cell apoptosis. Thus, this study identifies the myeloma autocrine Hh signaling pathway as a potential target for the treatment of MM. Targeting this pathway may improve the efficacy of chemotherapy in MM patients.

Vrbacky F, Nekvindova J, Rezacova V, et al.
Prognostic relevance of angiopoietin-2, fibroblast growth factor-2 and endoglin mRNA expressions in chronic lymphocytic leukemia.
Neoplasma. 2014; 61(5):585-92 [PubMed] Related Publications
Elevated levels of circulating angiogenic cytokines and increased expression of genes encoding angiogenic factors have been reported in recent years in patients with chronic lymphocytic leukemia (CLL) but data regarding prognostic and predictive significance are still limited. Therefore, in the present study based upon our prior pilot results, we measured mRNA expressions of angiopoietin-2 (Ang-2), fibroblast growth factor-2 (FGF-2) and endoglin (CD105) by reverse transcription quantitative PCR in purified CD19+ cells from 70 untreated CLL patients (median age, 63 years; males, 64%; Rai III/IV stages, 29 %; unmutated IgVH genes, 60 %) and evaluated their possible association with established prognostic factors and clinical course of the disease. Higher expression of Ang-2 was significantly associated with unmutated IgVH genes (n = 55, p = 0.003). Higher CD105 expression was significantly associated with unmutated IgVH genes (n = 55, p < 0.001), high CD38 expression (n = 66, p = 0.022), high ZAP-70 expression (n = 66, p = 0.010), Rai stage I-IV (n = 70, p < 0.001), progressive clinical course of CLL (n = 70, p = 0.001) and shorter time to treatment (n = 70; p < 0.001). Expression of FGF-2 was not significantly associated with any of the prognostic markers. These results indicate that elevated expression of Ang-2 and in particular CD105 by CLL cells is associated with unfavorable prognostic features and clinical outcome; thus, both cytokines appear to play an important role in biology and progression of CLL and warrant further investigation.

Pegram HJ, Purdon TJ, van Leeuwen DG, et al.
IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.
Leukemia. 2015; 29(2):415-22 [PubMed] Related Publications
Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19(+) tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.

Shim H, Ha JH, Lee H, et al.
Expression of myeloid antigen in neoplastic plasma cells is related to adverse prognosis in patients with multiple myeloma.
Biomed Res Int. 2014; 2014:893243 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
We evaluated the association between the expression of myeloid antigens on neoplastic plasma cells and patient prognosis. The expression status of CD13, CD19, CD20, CD33, CD38, CD56, and CD117 was analyzed on myeloma cells from 55 newly diagnosed patients, including 36 men (65%), of median age 61 years (range: 38-78). Analyzed clinical characteristics and laboratory parameters were as follows: serum β 2-microglobulin, lactate dehydrogenase, calcium, albumin, hemoglobin, serum creatinine concentrations, bone marrow histology, and cytogenetic findings. CD13+ and CD33+ were detected in 53% and 18%, respectively. Serum calcium (P = 0.049) and LDH (P = 0.018) concentrations were significantly higher and morphologic subtype of immature or plasmablastic was more frequent in CD33+ than in CD33- patients (P = 0.022). CD33 and CD13 expression demonstrate a potential prognostic impact and were associated with lower overall survival (OS; P = 0.001 and P = 0.025) in Kaplan-Meier analysis. Multivariate analysis showed that CD33 was independently prognostic of shorter progression free survival (PFS; P = 0.037) and OS (P = 0.001) with correction of clinical prognostic factors. This study showed that CD13 and CD33 expression associated with poor prognosis in patients with MM implicating the need of analysis of these markers in MM diagnosis.

Shi J, Li S, Zhou Y, et al.
Perioperative changes in peripheral regulatory B cells of patients with esophageal cancer.
Mol Med Rep. 2014; 10(3):1525-30 [PubMed] Related Publications
Current treatments for esophageal cancer (EC) rely on tumor eradication by surgery or chemoradiotherapy. However, such treatments do not account for the assessment and adjustment of the immune status of the patients. Regulatory B cells (Bregs) have been confirmed as a negative regulatory subtype in B‑cell populations. However, to the best of our knowledge, there have been no direct studies on Bregs in patients with EC. The present study enrolled sixty patients with EC and sixty healthy donors to detect the presence of Bregs in peripheral blood and to determine their clinical significance. The percentage of peripheral Bregs was measured using flow cytometry with fluorescence‑labeled antibodies against cluster of differentiation (CD) 5, CD19, interleukin (IL)‑10, forkhead box protein 3 (Foxp3) and transforming growth factor‑β1 (TGF‑β1) prior to and following radical surgery. The level of circulating Bregs in patients with EC was observed to be significantly higher than that in the healthy donors. However, this level was observed to decrease following surgery. The percentage of circulating TGF‑β‑producing Bregs and Foxp3‑expressing Bregs in patients with EC also decreased following surgery. By contrast, the percentage of peripheral IL‑10‑producing Bregs (B10s) significantly increased in patients with advanced EC following surgery. These findings suggest that Bregs have a negative immunoregulatory role in the development and progression of EC. Furthermore, postoperative combination therapies against Bregs, particularly B10s, may improve the outcome of patients with EC following resection.

Hojer C, Frankenberger S, Strobl LJ, et al.
B-cell expansion and lymphomagenesis induced by chronic CD40 signaling is strictly dependent on CD19.
Cancer Res. 2014; 74(16):4318-28 [PubMed] Related Publications
CD40, a member of the TNF receptor family, is expressed on all mature B cells and on most B-cell lymphomas. Recently, we have shown that constitutive activation of CD40 signaling in B cells induced by a fusion protein consisting of the transmembrane part of the Epstein-Barr viral latent membrane protein 1 (LMP1) and the cytoplasmic part of CD40 (LMP1/CD40) drives B-cell lymphoma development in transgenic mice. Because LMP1/CD40-expressing B cells showed an upregulation of CD19, we investigated CD19's function in CD40-driven B-cell expansion and lymphomagenesis. Here, we demonstrate that ablation of CD19 in LMP1/CD40 transgenic mice resulted in a severe loss and reduced lifespan of mature B cells and completely abrogated development of B-cell lymphoma. CD19 is localized to lipid rafts and constitutively activated by the LMP1/CD40 fusion protein in B cells. We provide evidence that the improved survival and malignant transformation of LMP1/CD40-expressing B cells are dependent on activation of the MAPK Erk that is mediated through CD19 in a PI3K-dependent manner. Our data suggest that constitutively active CD40 is dependent on CD19 to transmit survival and proliferation signals. Moreover, we detected a similarly functioning prosurvival pathway involving phosphorylated CD19 and PI3K-dependent Erk phosphorylation in human diffuse large B-cell lymphoma cell lines. Our data provide evidence that CD19 plays an important role in transmitting survival and proliferation signals downstream of CD40 and therefore might be an interesting therapeutic target for the treatment of lymphoma undergoing chronic CD40 signaling.

Myers DE, Yiv S, Qazi S, et al.
CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells.
Integr Biol (Camb). 2014; 6(8):766-80 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
We report the anti-leukemic potency of a unique biotargeted nanoscale liposomal nanoparticle (LNP) formulation of the spleen tyrosine kinase (SYK) P-site inhibitor C61. C61-loaded LNP were decorated with a murine CD19-specific monoclonal antibody directed against radiation-resistant CD19-receptor positive aggressive B-precursor acute lymphoblastic leukemia (ALL) cells. The biotargeted C61-LNP were more potent than untargeted C61-LNP and consistently caused apoptosis in B-precursor ALL cells. The CD19-directed C61-LNP also destroyed B-precursor ALL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. This unique nanostructural therapeutic modality targeting the SYK-dependent anti-apoptotic blast cell survival machinery shows promise for overcoming the clinical radiochemotherapy resistance of B-precursor ALL cells.

Fan D, Zhou X, Li Z, et al.
Stem cell programs are retained in human leukemic lymphoblasts.
Oncogene. 2015; 34(16):2083-93 [PubMed] Related Publications
Leukemic lymphoblasts within different immunophenotypic populations possess stem cell properties. However, whether or not the self-renewal program is retained from stem cells or conferred on progenitors by leukemogenic molecules remains unknown. We have addressed the issue in the context of TEL-AML1-associated acute lymphoblastic leukemia (ALL) by profiling a refined program edited from genes essential for self-renewal of hematopoietic stem cells and B-cell development. Bioinformatic analysis shows that ALL populations are loosely clustered and close to the normal population that contains stem and primitive progenitor cells. This finding indicates that immunophenotypes do not reflect maturation stages in ALL and that the self-renewal program may be retained from stem cells. Results of assessing 'first hit' function of TEL-AML1 in different populations of normal cells demonstrate the molecular model. Therefore, the current study shows a leukemogenic scenario of human ALL in which programs of stem cells are sustained in distinct fractions by leukemogenic mutations.

Bateman CM, Alpar D, Ford AM, et al.
Evolutionary trajectories of hyperdiploid ALL in monozygotic twins.
Leukemia. 2015; 29(1):58-65 [PubMed] Related Publications
Identical twins have provided unique insights on timing or sequence of genetic events in acute lymphoblastic leukaemia (ALL). To date, this has mainly focused on ALL with MLL or ETV6-RUNX1 fusions, with hyperdiploid ALL remaining less well characterised. We examined three pairs of monozygotic twins, two concordant and one discordant for hyperdiploid ALL, for single-nucleotide polymorphism (SNP)-defined copy number alterations (CNAs), IGH/L plus TCR gene rearrangements and mutations in NRAS, KRAS, FLT3 and PTPN11 genes. We performed whole exome sequencing in one concordant twin pair. Potential 'driver' CNAs were low, 0-3 per case, and all were different within a pair. One patient had an NRAS mutation that was lacking from leukaemic cells of the twin sibling. By exome sequencing, there were 12 nonsynonymous mutations found in one twin and 5 in the other, one of which in SCL44A2 was shared or identical. Concordant pairs had some identical IGH/L and TCR rearrangements. In the twin pair with discordant hyperdiploid ALL, the healthy co-twin had persistent low level hyperdiploid CD19+ cells that lacked a CNA present in the ALL cells of her sibling. From these data, we propose that hyperdiploid ALL arises in a pre-B cell in utero and mutational changes necessary for clinical ALL accumulate subclonally and postnatally.

Baboolal TG, Boxall SA, Churchman SM, et al.
Intrinsic multipotential mesenchymal stromal cell activity in gelatinous Heberden's nodes in osteoarthritis at clinical presentation.
Arthritis Res Ther. 2014; 16(3):R119 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
INTRODUCTION: Gelatinous Heberden's nodes (HNs), also termed synovial cysts, are a common form of generalized osteoarthritis (OA). We sought to determine whether HN cases at clinical presentation contained multipotential stromal cells (MSCs) and to explore whether such cells were more closely related to bone marrow (BM) or synovial fluid (SF) MSCs by transcriptional analysis.
METHODS: At clinical presentation, gelatinous material was extracted/extruded from the distal phalangeal joint of OA patients with HNs. From this, plastic adherent cells were culture-expanded for phenotypic and functional characterization and comparison with BM- and SF-MSCs. Mesenchymal related gene expression was studied by using a custom-designed TaqMan Low Density Array to determine transcriptional similarities between different MSC groups and skin fibroblasts.
RESULTS: In all cases, HN material produced MSC-like colonies. Adherent cultures displayed an MSC phenotype (CD29(+), CD44(+), CD73(+), CD81(+), and CD90(+) and CD14(-) CD19(-), CD31(-), CD34(-), CD45(-), and HLADR(-)) and exhibited osteogenic, chondrogenic lineage differentiation but weak adipogenesis. Gene cluster analysis showed that HN-MSCs were more closely related to SF- than normal or OA BM-MSCs with significantly higher expression of synovium-related gene markers such as bone morphogenic protein 4 (BMP4), bone morphogenetic protein receptor type 1A (BMPR1A), protein/leucine-rich end leucine-rich repeat protein (PRELP), secreted frizzled-related protein 4 (SFRP4), and tumor necrosis factor alpha-induced protein 6 (TNFAIP6) (P <0.05).
CONCLUSIONS: Gelatinous HNs derived from hand OA at clinical presentation contain a population of MSCs that share transcriptional similarities with SF-derived MSCs. Their aberrant entrapment within the synovial cysts may impact on their normal role in joint homeostasis.

Sánchez-Rodríguez R, Torres-Mena JE, De-la-Luz-Cruz M, et al.
Increased expression of prostaglandin reductase 1 in hepatocellular carcinomas from clinical cases and experimental tumors in rats.
Int J Biochem Cell Biol. 2014; 53:186-94 [PubMed] Related Publications
To identify novel tumor-associated proteins, we analyzed the protein expression patterns from experimental hepatocellular carcinoma (HCC) that were induced using hepatocarcinogenesis models in rats. Rats were subjected to two previously described protocols of hepatocarcinogenesis using diethylnitrosamine as a carcinogen: the alternative Solt-Farber (aS&F) protocol, which induces HCC within 9 months, and Schiffer's model, which induces cirrhosis and multifocal HCC within 18 weeks. The patterns of protein expression from tumors and normal liver tissue were examined by SDS-PAGE and the bands identified at 33-34 kDa were analyzed by mass spectrometry. The prostaglandin reductase 1 (PTGR1) showed the highest number of peptides, with a confidence of level >99%. The increased expression of PTGR1 in tumors was confirmed in these two models by Western blotting and by increase in alkenal/one oxidoreductase activity (25-fold higher than normal liver). In addition, the gene expression level of Ptgr1, as measured by qRT-PCR, was increased during cancer development in a time-dependent manner (200-fold higher than normal liver). Furthermore, PTGR1 was detected in the cytoplasm of neoplastic cells in rat tumors and in 12 human HCC cases by immunohistochemistry. These analyses were performed by comparing the expression of PTGR1 to that of two well-known markers of hepatocarcinoma, Glutathione S-transferase pi 1 (GSTP1) in rats and glypican-3 in humans. The increased expression and activity of PTGR1 in liver carcinogenesis encourage further research aimed at understanding the metabolic role of PTGR1 in HCC and its potential application for human cancer diagnosis and treatment.

Zhou Y, Liu X, Xu L, et al.
Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over-expression of the ETS factor SPIB in Waldenström macroglobulinaemia.
Br J Haematol. 2014; 166(5):677-89 [PubMed] Related Publications
In Waldenström macroglobulinaemia (WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID2 were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells (LPC). Ectopic expression of SPIB in healthy donor CD19(+) cells inhibited plasmacytic differentiation in conjunction with decreased transcription of IRF4 and XBP1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM1, XBP1 spliced form, IRF4 and ID2. Knock-down of SPIB also led to decreased BCL2 expression. Given that SPIB is a direct target of POU2AF1 (OBF1) in complex with POU2F2 or POU2F1, we next examined their expression in WM LPC. POU2F2 transcription, as well as POU2F2 and POU2AF1 protein expression was higher in WM LPC. Ectopic expression of POU2F2 in healthy donor CD19(+) cells induced transcription of SPIB and suppressed transcription of PRDM1 and IRF4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2AF1 in SPIB and ID2 promoters. These findings establish a molecular hierarchy among POU2F2, SPIB and ID2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM.

Xu Y, Zhang M, Ramos CA, et al.
Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15.
Blood. 2014; 123(24):3750-9 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Adoptive transfer of T lymphocytes expressing a CD19-specific chimeric antigen receptor (CAR.CD19) induces complete tumor regression in patients with lymphoid malignancies. Although in vivo persistence of CAR-T cells correlates with clinical responses, it remains unknown whether specific cell subsets within the CAR-T-cell product correlate with their subsequent in vivo expansion and persistence. We analyzed 14 patients with B-cell malignancies infused with autologous CAR.CD19-redirected T cells expanded ex vivo using IL-2, and found that their in vivo expansion only correlated with the frequency within the infused product of a CD8(+)CD45RA(+)CCR7(+) subset, whose phenotype is closest to "T-memory stem cells." Preclinical models showed that increasing the frequency of CD8(+)CD45RA(+)CCR7(+) CAR-T cells in the infused line by culturing the cells with IL-7 and IL-15 produced greater antitumor activity of CAR-T cells mediated by increased resistance to cell death, following repetitive encounters with the antigen, while preserving their migration to secondary lymphoid organs. This trial was registered at as #NCT00586391 and #NCT00709033.

Wrobel T, Pogrzeba J, Stefanko E, et al.
Expression of Eph A4, Eph B2 and Eph B4 receptors in AML.
Pathol Oncol Res. 2014; 20(4):901-7 [PubMed] Related Publications
Eph receptors represent the largest subfamily of receptor tyrosine kinases (RTKs). The up- regulation of Eph receptors has been documented in various solid tumors, where it often correlates with poor prognosis. Their significance in hematologic malignancies is still unclear. This study aimed to investigate the expression of Eph A4, Eph B2, and Eph B4 mRNA in non - M3 AML patients and determine their prognostic significance. Bone marrow samples from 101 newly diagnosed non - M3 AML patients and 26 healthy controls for comparison were quantified by real time reverse transcriptase polymerase chain reaction (RT-PCR), and the comparative cycle threshold (Ct) method was used to determine their relative expression levels to GUS control gene. The results showed that expression of all selected Eph receptors was significantly lower in AML patients comparing to controls. It also differed according to FAB subtypes. The decreased expression levels of Eph A4 were associated with higher leukocytes (p = 0.022) and blast cell counts (p = 0.001), and unfavorable FLT3-ITD mutation. Our study revealed significant correlation between lower EphB2 expression levels, and higher complete remission rate (p = 0.009724) and longer overall survival. Additionally, we found that patients with shorter RFS had decreased EphB4 expression (p = 0.00). In conclusion, the results suggest the prognostic impact of decreased expression levels of some Eph receptors in AML patients.

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