publication . Article . Other literature type . 2017

Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells

Roberto CHIARLE; Teresa Poggio; Feilong Meng;
Open Access
  • Published: 01 Jan 2017 Journal: Nature, volume 542, pages 489-493 (issn: 0028-0836, eissn: 1476-4687, Copyright policy)
  • Publisher: Springer Science and Business Media LLC
Abstract
PI3Kδ controls the expression of the recombinogenic enzyme AID; excessive AID activity caused by PI3Kδ inhibition can induce genomic instability in leukaemia and lymphoma cells, as well as in patients with chronic lymphocytic leukaemia treated with PI3Kδ inhibitors. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway is highly active in many types of cancer. Several PI3Kδ inhibitors have been approved for the treatment of B-cell cancers such as leukaemias and lymphomas. Besides its cancer-promoting effects, PI3Kδ also controls the activity of the activation-induced cytidine deaminase (AID) enzyme, which promotes DNA recombination. Excessive AID activity due to P...
Subjects
free text keywords: Multidisciplinary, Medicine (all); Multidisciplinary, Article
Funded by
NIH| ITSC for Leukemia: Novel Molecular Strategies for NCTN: Individualized Therapie
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U10CA180861-01
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| AID Targeting Mechanisms for IgH Switch Recombination and Somatic Hypermutation
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01AI077595-08
  • Funding stream: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
,
NIH| Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA196703-03
  • Funding stream: NATIONAL CANCER INSTITUTE
43 references, page 1 of 3

Alt, FW, Zhang, Y, Meng, FL, Guo, C, Schwer, B. Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell. 2013; 152: 417-429 [OpenAIRE] [PubMed]

Nussenzweig, A, Nussenzweig, MC. Origin of chromosomal translocations in lymphoid cancer. Cell. 2010; 141: 27-38 [OpenAIRE] [PubMed]

Robbiani, DF. AID Produces DNA Double-Strand Breaks in Non-Ig Genes and Mature B Cell Lymphomas with Reciprocal Chromosome Translocations. Molecular cell. 2009; 36: 631-641 [OpenAIRE] [PubMed]

Omori, SA. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity. 2006; 25: 545-557 [PubMed]

Byrd, JC. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. The New England journal of medicine. 2013; 369: 32-42 [OpenAIRE] [PubMed]

Gopal, AK. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. The New England journal of medicine. 2014; 370: 1008-1018 [OpenAIRE] [PubMed]

Brown, JR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014; 123: 3390-3397 [OpenAIRE] [PubMed]

Dong, S. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014; 124: 3583-3586 [OpenAIRE] [PubMed]

Chiarle, R. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011; 147: 107-119 [OpenAIRE] [PubMed]

Meng, FL. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell. 2014; 159: 1538-1548 [OpenAIRE] [PubMed]

Advani, RH. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013; 31: 88-94 [OpenAIRE] [PubMed]

Rush, JS, Liu, M, Odegard, VH, Unniraman, S, Schatz, DG. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102: 13242-13247 [OpenAIRE] [PubMed]

Angulo, I. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013; 342: 866-871 [OpenAIRE] [PubMed]

Lucas, CL. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nature immunology. 2014; 15: 88-97 [OpenAIRE] [PubMed]

Klein, IA. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011; 147: 95-106 [OpenAIRE] [PubMed]

43 references, page 1 of 3
Related research
Abstract
PI3Kδ controls the expression of the recombinogenic enzyme AID; excessive AID activity caused by PI3Kδ inhibition can induce genomic instability in leukaemia and lymphoma cells, as well as in patients with chronic lymphocytic leukaemia treated with PI3Kδ inhibitors. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway is highly active in many types of cancer. Several PI3Kδ inhibitors have been approved for the treatment of B-cell cancers such as leukaemias and lymphomas. Besides its cancer-promoting effects, PI3Kδ also controls the activity of the activation-induced cytidine deaminase (AID) enzyme, which promotes DNA recombination. Excessive AID activity due to P...
Subjects
free text keywords: Multidisciplinary, Medicine (all); Multidisciplinary, Article
Funded by
NIH| ITSC for Leukemia: Novel Molecular Strategies for NCTN: Individualized Therapie
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U10CA180861-01
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| AID Targeting Mechanisms for IgH Switch Recombination and Somatic Hypermutation
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01AI077595-08
  • Funding stream: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
,
NIH| Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA196703-03
  • Funding stream: NATIONAL CANCER INSTITUTE
43 references, page 1 of 3

Alt, FW, Zhang, Y, Meng, FL, Guo, C, Schwer, B. Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell. 2013; 152: 417-429 [OpenAIRE] [PubMed]

Nussenzweig, A, Nussenzweig, MC. Origin of chromosomal translocations in lymphoid cancer. Cell. 2010; 141: 27-38 [OpenAIRE] [PubMed]

Robbiani, DF. AID Produces DNA Double-Strand Breaks in Non-Ig Genes and Mature B Cell Lymphomas with Reciprocal Chromosome Translocations. Molecular cell. 2009; 36: 631-641 [OpenAIRE] [PubMed]

Omori, SA. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity. 2006; 25: 545-557 [PubMed]

Byrd, JC. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. The New England journal of medicine. 2013; 369: 32-42 [OpenAIRE] [PubMed]

Gopal, AK. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. The New England journal of medicine. 2014; 370: 1008-1018 [OpenAIRE] [PubMed]

Brown, JR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014; 123: 3390-3397 [OpenAIRE] [PubMed]

Dong, S. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014; 124: 3583-3586 [OpenAIRE] [PubMed]

Chiarle, R. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011; 147: 107-119 [OpenAIRE] [PubMed]

Meng, FL. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell. 2014; 159: 1538-1548 [OpenAIRE] [PubMed]

Advani, RH. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013; 31: 88-94 [OpenAIRE] [PubMed]

Rush, JS, Liu, M, Odegard, VH, Unniraman, S, Schatz, DG. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102: 13242-13247 [OpenAIRE] [PubMed]

Angulo, I. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013; 342: 866-871 [OpenAIRE] [PubMed]

Lucas, CL. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nature immunology. 2014; 15: 88-97 [OpenAIRE] [PubMed]

Klein, IA. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011; 147: 95-106 [OpenAIRE] [PubMed]

43 references, page 1 of 3
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