Attenuating homologous recombination stimulates an AID-induced antileukemic effect

Lamont, Kristin; Hasham, Muneer G.; Donghia, Nina M.; Branca, Jane; Chavaree, Margaret; Chase, Betsy; Breggia, Anne; Hedlund, Jacquelyn; Emery, Ivette F.; Cavallo, Francesca; Jasin, Maria; Rüter, Jens; Mills, Kevin D.

doi:10.1084/jem.20121258

Cited by 34 publications

(44 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By inhibiting RAD51-mediated HR repair of AID-initiated off-target DSBs, treatment with the small molecule DIDS induces the death of B-lymphocytes in which SHM and CSR processes have been initiated (23). Therefore, we hypothesized targeting the AID/RAD51 pathway by DIDS treatment might provide an effective B-lymphocyte-directed T1D intervention.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, AID generates DSBs elsewhere throughout the genome (22, 23), that are normally repaired by RAD51 complex-mediated homologous recombination (HR). In the absence of HR, B-lymphocytes in which SHM/CSR has been initiated undergo cell death (23). The small molecule 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) inhibits RAD51-mediated HR (23).…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of HR, B-lymphocytes in which SHM/CSR has been initiated undergo cell death (23). The small molecule 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) inhibits RAD51-mediated HR (23). DIDS has been used as a model agent in previous studies indicating RAD51 blockade could be considered as an intervention for eliminating AID-positive B-cell lymphomas (23).…”

Section: Introductionmentioning

confidence: 99%

“…The small molecule 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) inhibits RAD51-mediated HR (23). DIDS has been used as a model agent in previous studies indicating RAD51 blockade could be considered as an intervention for eliminating AID-positive B-cell lymphomas (23). Here we utilized DIDS treatment to determine whether targeting the AID/RAD51 axis could provide a B-lymphocyte-directed intervention for T1D.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

Ratiu

Racine

Hasham

et al. 2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

B-lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APC preferentially supporting 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, B-lymphocyte-directed T1D interventions tested to date failed to halt β-cell demise. IgG autoantibodies marking humans at future T1D risk indicate B-lymphocytes producing them have undergone the affinity maturation processes of class switch recombination (CSR) and possibly somatic hypermutation (SHM). This study found that CRISPR/Cas9-mediated ablation of the Aicda gene required for CSR/SHM induction, inhibits T1D development in the NOD mouse model. The Aicda encoded AID molecule induces genome-wide DNA breaks that, if not repaired through RAD51-mediated homologous recombination (HR), result in B-lymphocyte death. Treatment with the RAD51 inhibitor 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) also strongly inhibited T1D development in NOD mice. Both the genetic and small molecule-targeting approaches expanded CD73+ B-lymphocytes exerting 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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

Ratiu

Racine

Hasham

et al. 2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…56,57 More than 40% of CLLs have marked expression of AID , and in these cases inhibition of homologous recombination in vitro preferentially induced apoptosis in leukemia cells. 58 …”

Section: Clinical Implications Of Genomic Discoveries In Cllmentioning

confidence: 99%

Evolving Understanding of the CLL Genome

Gruber

2014

Seminars in Hematology

View full text Add to dashboard Cite

Over the past few years, massively parallel sequencing technologies have revealed with high resolution the tremendous genetic and epigenetic heterogeneity in chronic lymphocytic leukemia (CLL). We have learned how the molecular architecture differs not only between affected individuals but also within samples and over time. These insights have catalyzed our understanding of the pathobiology of CLL and point to critical signaling pathways in the development and progression of the disease. Several key driver alterations have been identified, which serve to refine prognostic schemata but also inspire the development of new therapeutic strategies. Ongoing advances in technology promise to further elucidate the molecular basis of CLL, and this knowledge is anticipated to aid us in understanding and addressing the clinical challenge presented by the vast variability in the clinical course of patients with CLL.

show abstract

Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy?

Budke

Kozikowski

et al. 2016

ChemMedChem

View full text Add to dashboard Cite

Homologous recombination (HR) is an evolutionarily conserved DNA repair process. Overexpression of the key HR protein RAD51 is a common feature of malignant cells. RAD51 plays two distinct genome-stabilizing roles, including HR-mediated repair of double-strand breaks (DSBs) and the promotion of replication fork stability during replication stress. Because upregulation of RAD51 in cancer cells can promote tumor resistance to DNA-damaging oncologic therapies, we and others have worked to develop cancer therapeutics that target various aspects of RAD51 protein function. Herein, we provide an overview of recent developments in this field, together with our perspectives on the challenges associated with these evolving anticancer strategies.

show abstract

Attenuating homologous recombination stimulates an AID-induced antileukemic effect

Abstract: Inhibition of the RAD51 homologous recombination factor prevents the repair of AID-initiated DNA breaks and induces apoptosis preferentially in AID-expressing human CLL.

Cited by 34 publications

References 51 publications

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

Evolving Understanding of the CLL Genome

Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy?

Contact Info

Product

Resources

About