Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 9, Pages 3495-3500Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1222863110
Keywords
leukemogenesis; PKA pathway; PML/RAR alpha; SMRT; NcoR1
Categories
Funding
- Chinese National Key Basic Research Project (973) [2013CB966800, 2010CB529200]
- Mega-Projects of Science Research for the 12th Five-Year Plan [2013ZX09303302]
- Ministry of Health [201202003]
- National High Tech Program for Biotechnology Grant 863 [2012AA02A505]
- National Natural Science Foundation of China [30830119, 81170506, 81270624]
- Shanghai Rising Star Program [11QA1404300]
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The refractoriness of acute promyelocytic leukemia (APL) with t(11;17)(q23;q21) to all-trans retinoic acid (ATRA)-based therapy concerns clinicians and intrigues basic researchers. By using a murine leukemic model carrying both promyelocytic leukemia zinc finger/retinoic acid receptor-alpha (PLZF/RAR alpha) and RAR alpha/PLZF fusion genes, we discovered that 8-chlorophenylthio adenosine-3', 5'-cyclic monophosphate (8-CPT-cAMP) enhances cellular differentiation and improves gene trans-activation by ATRA in leukemic blasts. Mechanistically, in combination with ATRA, 8-CPT-cAMP activates PKA, causing phosphorylation of PLZF/RAR alpha at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RAR alpha. This process results in changes of local chromatin and transcriptional reactivation of the retinoic acid pathway in leukemic cells. Meanwhile, 8-CPT-cAMP also potentiated ATRA-induced degradation of PLZF/RAR alpha through its Ser765 phosphorylation. In vivo treatment of the t(11;17) APL mouse model demonstrated that 8-CPT-cAMP could significantly improve the therapeutic effect of ATRA by targeting a leukemia-initiating cell activity. This combined therapy, which induces enhanced differentiation and oncoprotein degradation, may benefit t(11;17) APL patients.
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