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Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy.
Liu, Yao-Chung; Kwon, Junsu; Fabiani, Emiliano; Xiao, Zhijian; Liu, Yanjing V; Follo, Matilde Y; Liu, Jinqin; Huang, Huijun; Gao, Chong; Liu, Jun; Falconi, Giulia; Valentini, Lia; Gurnari, Carmelo; Finelli, Carlo; Cocco, Lucio; Liu, Jin-Hwang; Jones, Adrianna I; Yang, Junyu; Yang, Henry; Thoms, Julie A I; Unnikrishnan, Ashwin; Pimanda, John E; Pan, Rongqing; Bassal, Mahmoud A; Voso, Maria T; Tenen, Daniel G; Chai, Li.
Afiliación
  • Liu YC; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Kwon J; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Fabiani E; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Xiao Z; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Liu YV; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Follo MY; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Liu J; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Huang H; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Gao C; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Liu J; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Falconi G; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Valentini L; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Gurnari C; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Finelli C; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Cocco L; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Liu JH; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Jones AI; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Yang J; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Yang H; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Thoms JAI; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Unnikrishnan A; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Pimanda JE; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Pan R; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Bassal MA; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Voso MT; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Tenen DG; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
  • Chai L; From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematol
N Engl J Med ; 386(21): 1998-2010, 2022 05 26.
Article en En | MEDLINE | ID: mdl-35613022
ABSTRACT

BACKGROUND:

Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated.

METHODS:

We examined the effect of hypomethylating agents on SALL4, a known oncogene that plays an important role in myelodysplastic syndrome and other cancers. Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in SALL4 expression, treatment response, and clinical outcome. Leukemic cell lines with low or undetectable SALL4 expression were used to study the relationship between SALL4 methylation and expression. A locus-specific demethylation technology, CRISPR-DNMT1-interacting RNA (CRISPR-DiR), was used to identify the CpG island that is critical for SALL4 expression.

RESULTS:

SALL4 up-regulation after treatment with hypomethylating agents was observed in 10 of 25 patients (40%) in cohort 1 and in 13 of 43 patients (30%) in cohort 2 and was associated with a worse outcome. Using CRISPR-DiR, we discovered that demethylation of a CpG island within the 5' untranslated region was critical for SALL4 expression. In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and up-regulation of SALL4 expression.

CONCLUSIONS:

By combining analysis of patient samples with CRISPR-DiR technology, we found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent can indeed occur and should be further studied. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Oncogenes / Síndromes Mielodisplásicos / Regulación hacia Arriba / Desmetilación / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: N Engl J Med Año: 2022 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Oncogenes / Síndromes Mielodisplásicos / Regulación hacia Arriba / Desmetilación / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: N Engl J Med Año: 2022 Tipo del documento: Article