دورية أكاديمية
أعرض في EDS

Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts.

التفاصيل البيبلوغرافية
العنوان: Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts.
المؤلفون: Ellegast JM; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Alexe G; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Bioinformatics Graduate Program, Boston University, Boston, Massachusetts., Hamze A; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Lin S; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Uckelmann HJ; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Rauch PJ; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Pimkin M; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Ross LS; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Dharia NV; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Robichaud AL; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Conway AS; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Khalid D; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Perry JA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Wunderlich M; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio., Benajiba L; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; Université de Paris, INSERM U944 and CNRS 7212, Institut de Recherche Saint Louis, Hôpital Saint Louis, APHP, Paris, France., Pikman Y; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Nabet B; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington., Gray NS; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, California., Orkin SH; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Stegmaier K; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
المصدر: Cancer discovery [Cancer Discov] 2022 Jul 06; Vol. 12 (7), pp. 1760-1781.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research
مواضيع طبية MeSH: Leukemia, Myeloid, Acute*/genetics, Humans ; Inflammation/genetics ; NF-kappa B/metabolism ; Signal Transduction
مستخلص: Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells implicated in inflammatory pathways. We identified the immune modulator IRF2BP2 as a selective AML dependency. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene-expression studies demonstrated that IRF2BP2 represses IL1β/TNFα signaling via NFκB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.
Significance: This study exploits inflammatory programs inherent to AML blasts to identify genetic vulnerabilities in this disease. In doing so, we determined that AML cells are dependent on the transcriptional repressive activity of IRF2BP2 for their survival, revealing cell-intrinsic inflammation as a mechanism priming leukemic blasts for regulated cell death. See related commentary by Puissant and Medyouf, p. 1617. This article is highlighted in the In This Issue feature, p. 1599.
(©2022 American Association for Cancer Research.)
التعليقات: Comment in: Cancer Discov. 2022 Jul 6;12(7):1617-1619. (PMID: 35791696)
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معلومات مُعتمدة: K99 CA263161 United States CA NCI NIH HHS; P50 CA206963 United States CA NCI NIH HHS; R50 CA211404 United States CA NCI NIH HHS; R35 CA210030 United States CA NCI NIH HHS; K22 CA258805 United States CA NCI NIH HHS; K08 CA222684 United States CA NCI NIH HHS
المشرفين على المادة: 0 (NF-kappa B)
تواريخ الأحداث: Date Created: 20220411 Date Completed: 20220708 Latest Revision: 20230107
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9308469
DOI: 10.1158/2159-8290.CD-21-0956
PMID: 35405016
قاعدة البيانات: MEDLINE
الوصف
تدمد:2159-8290
DOI:10.1158/2159-8290.CD-21-0956