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Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.
Choi, Jaewoo; Ceribelli, Michele; Phelan, James D; Häupl, Björn; Huang, Da Wei; Wright, George W; Hsiao, Tony; Morris, Vivian; Ciccarese, Francesco; Wang, Boya; Corcoran, Sean; Scheich, Sebastian; Yu, Xin; Xu, Weihong; Yang, Yandan; Zhao, Hong; Zhou, Joyce; Zhang, Grace; Muppidi, Jagan; Inghirami, Giorgio G; Oellerich, Thomas; Wilson, Wyndham H; Thomas, Craig J; Staudt, Louis M.
Affiliation
  • Choi J; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Ceribelli M; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
  • Phelan JD; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Häupl B; Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany.
  • Huang DW; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Wright GW; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Hsiao T; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Morris V; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Ciccarese F; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata 64, 35128 Padova, Italy.
  • Wang B; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Corcoran S; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Scheich S; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany; Universit
  • Yu X; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Xu W; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Yang Y; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Zhao H; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Zhou J; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Zhang G; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Muppidi J; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Inghirami GG; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • Oellerich T; Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany.
  • Wilson WH; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Thomas CJ; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
  • Staudt LM; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: lstaudt@mail.nih.gov.
Cancer Cell ; 42(5): 833-849.e12, 2024 May 13.
Article in En | MEDLINE | ID: mdl-38701792
ABSTRACT
Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Antigen, B-Cell / Glucocorticoids Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2024 Document type: Article Affiliation country: Country of publication:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Antigen, B-Cell / Glucocorticoids Limits: Animals / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2024 Document type: Article Affiliation country: Country of publication: