Activation of Notch and Myc Signaling via B-cell-Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia.

Autor:	Biran A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Yin S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Kretzmer H; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany., Ten Hacken E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Parvin S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Lucas F; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Uduman M; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Gutierrez C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Dangle N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Billington L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Regis FF; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Rassenti LZ; Moores Cancer Center, University of California San Diego Health, La Jolla, California., Mohammad A; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Hoffmann GB; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Stevenson K; Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Zheng M; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Witten E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Fernandes SM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Tausch E; Department of Internal Medicine III, Ulm University, Ulm, Germany., Sun C; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland., Stilgenbauer S; Department of Internal Medicine III, Ulm University, Ulm, Germany., Brown JR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Kipps TJ; Moores Cancer Center, University of California San Diego Health, La Jolla, California., Aster JC; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Gnirke A; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Neuberg DS; Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Letai A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Wang L; Department of Systems Biology, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Monrovia, California., Carrasco RD; Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Meissner A; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts., Wu CJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. cwu@partners.org.; Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Dec 15; Vol. 81 (24), pp. 6117-6130. Date of Electronic Publication: 2021 Oct 22.
DOI:	10.1158/0008-5472.CAN-21-1273
Abstrakt:	Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yields a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haploinsufficient tumor suppressor. B1a cells were confirmed as the cell of origin of disease in this model, and Dnmt3a depletion resulted in focal hypomethylation and activation of Notch and Myc signaling. Amplification of chromosome 15 containing the Myc gene was detected in all CLL mice tested, and infiltration of high- Myc -expressing CLL cells in the spleen was observed. Notably, hyperactivation of Notch and Myc signaling was exclusively observed in the Dnmt3a CLL mice, but not in three other CLL mouse models tested ( Sf3b1-Atm , Ikzf3 , and MDR ), and Dnmt3a -depleted CLL were sensitive to pharmacologic inhibition of Notch signaling in vitro and in vivo . Consistent with these findings, human CLL samples with lower DNMT3A expression were more sensitive to Notch inhibition than those with higher DNMT3A expression. Altogether, these results suggest that Dnmt3a depletion induces CLL that is highly dependent on activation of Notch and Myc signaling. SIGNIFICANCE: Loss of DNMT3A expression is a driving event in CLL and is associated with aggressive disease, activation of Notch and Myc signaling, and enhanced sensitivity to Notch inhibition. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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