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1.
Genes Cancer ; 11(1-2): 83-94, 2020.
Article in English | MEDLINE | ID: mdl-32577159

ABSTRACT

Known as the guardian of the genome, transformation-related protein 53 (TRP53) is a well -known tumor suppressor. Here, we describe a novel TRP53 deficient mouse model on a tumor prone background-SJL/J mice. The absence of TRP53 (TRP53 nullizygosity) leads to a shift in the tumor spectrum from a non-Hodgkin's-like disease to thymic lymphomas and testicular teratomas at a very rapid tumor onset averaging ~12 weeks of age. In haplotype studies, comparing tumor prone versus tumor resistant Trp53 null mouse strains, we found that other tumor suppressor, DNA repair and/or immune system genes modulate tumor incidence in TRP53 null strains, suggesting that even a strong tumor suppressor such as TRP53 is modulated by genetic background. Due to their rapid development of tumors, the SJL/J TRP53 null mice generated here can be used as an efficient chemotherapy or immunotherapy screening mouse model.

2.
Cancer Biol Ther ; 20(2): 169-182, 2019.
Article in English | MEDLINE | ID: mdl-30183475

ABSTRACT

Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor. Next, we tested the cancer-cell specificity of a therapeutic compound using the MEC1 cell line, a chronic lymphocytic leukemia (CLL) cell line that expresses activation induced cytidine deaminase (AID). We show that MEC1 cells, are susceptible to 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), a specific RAD51 inhibitor. We then combine 2DG and DIDS, each at a lower dose and demonstrate that this combination is more efficacious than fludarabine, the current standard- of- care treatment for CLL. This suggests that the therapeutic blockade of glycolysis together with the therapeutic inhibition of RAD51-dependent homologous recombination can be a potentially beneficial combination for targeting AID positive cancer cells with minimal adverse effects on normal tissue. Implications: Combination therapy targeting glycolysis and specific RAD51 function shows increased efficacy as compared to standard of care treatments in leukemias.


Subject(s)
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Deoxyglucose/pharmacology , Neoplasms/drug therapy , Rad51 Recombinase/antagonists & inhibitors , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/administration & dosage , Animals , Cell Line, Tumor , Deoxyglucose/administration & dosage , Drug Synergism , Female , Glycolysis/drug effects , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Neoplasms/metabolism , Rad51 Recombinase/metabolism , Xenograft Model Antitumor Assays
3.
J Immunol ; 198(11): 4255-4267, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28461573

ABSTRACT

B lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APCs preferentially supporting the expansion of autoreactive pathogenic T cells. As a result of their pathogenic importance, B lymphocyte-targeted therapies have received considerable interest as potential T1D interventions. Unfortunately, the B lymphocyte-directed T1D interventions tested to date failed to halt ß cell demise. IgG autoantibodies marking humans at future risk for T1D indicate that B lymphocytes producing them have undergone the affinity-maturation processes of class switch recombination and, possibly, somatic hypermutation. This study found that CRISPR/Cas9-mediated ablation of the activation-induced cytidine deaminase gene required for class switch recombination/somatic hypermutation induction inhibits T1D development in the NOD mouse model. The activation-induced cytidine deaminase protein induces genome-wide DNA breaks that, if not repaired through RAD51-mediated homologous recombination, result in B lymphocyte death. Treatment with the RAD51 inhibitor 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid also strongly inhibited T1D development in NOD mice. The genetic and small molecule-targeting approaches expanded CD73+ B lymphocytes that exert regulatory activity suppressing diabetogenic T cell responses. Hence, an initial CRISPR/Cas9-mediated genetic modification approach has identified the AID/RAD51 axis as a target for a potentially clinically translatable pharmacological approach that can block T1D development by converting B lymphocytes to a disease-inhibitory CD73+ regulatory state.


Subject(s)
B-Lymphocytes, Regulatory/immunology , Carrier Proteins/antagonists & inhibitors , Cytidine Deaminase/antagonists & inhibitors , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/prevention & control , Lymphocyte Activation , Nuclear Proteins/antagonists & inhibitors , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , 5'-Nucleotidase/immunology , Animals , Autoantibodies/immunology , CRISPR-Cas Systems , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , DNA-Binding Proteins , Diabetes Mellitus, Experimental , Immunoglobulin Class Switching , Mice , Mice, Inbred NOD , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , RNA-Binding Proteins , Somatic Hypermutation, Immunoglobulin
4.
J Immunol ; 189(5): 2374-82, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22826323

ABSTRACT

Activation-induced cytidine deaminase (AID) initiates DNA double-strand breaks (DSBs) in the IgH gene (Igh) to stimulate isotype class switch recombination (CSR), and widespread breaks in non-Igh (off-target) loci throughout the genome. Because the DSBs that initiate class switching occur during the G1 phase of the cell cycle, and are repaired via end joining, CSR is considered a predominantly G1 reaction. By contrast, AID-induced non-Igh DSBs are repaired by homologous recombination. Although little is known about the connection between the cell cycle and either induction or resolution of AID-mediated non-Igh DSBs, their repair by homologous recombination implicates post-G1 phases. Coordination of DNA breakage and repair during the cell cycle is critical to promote normal class switching and prevent genomic instability. To understand how AID-mediated events are regulated through the cell cycle, we have investigated G1-to-S control in AID-dependent genome-wide DSBs. We find that AID-mediated off-target DSBs, like those induced in the Igh locus, are generated during G1. These data suggest that AID-mediated DSBs can evade G1/S checkpoint activation and persist beyond G1, becoming resolved during S phase. Interestingly, DSB resolution during S phase can promote not only non-Igh break repair, but also Ig CSR. Our results reveal novel cell cycle dynamics in response to AID-initiated DSBs, and suggest that the regulation of the repair of these DSBs through the cell cycle may ensure proper class switching while preventing AID-induced genomic instability.


Subject(s)
Cytidine Deaminase/physiology , DNA Breaks, Double-Stranded , Immunoglobulin Class Switching/genetics , Immunoglobulin Isotypes/genetics , S Phase/genetics , S Phase/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Cells, Cultured , Cytidine Deaminase/deficiency , Cytidine Deaminase/genetics , DNA Repair/genetics , DNA Repair/immunology , G1 Phase/genetics , G1 Phase/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout
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