Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.
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http://dx.doi.org/10.3324/haematol.2020.274878 | DOI Listing |
Biochem Pharmacol
December 2024
Zhongshan Hospital Institute of Clinical Science, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address:
B-cell lymphoma extra large (BCL-X) is an important anti-apoptotic protein of BCL-2 family. It is frequently overexpressed in various hematologic and solid tumors, often positively correlated with chemotherapy resistance in tumors. However, the clinical development of the small molecule BCL-X inhibitor ABT-263 has been challenged on account of its on-target and dose-limiting toxicity.
View Article and Find Full Text PDFBioorg Med Chem Lett
December 2024
Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address:
FLT3-ITD and TKD mutants play a central role in acute myeloid leukemia (AML), making FLT3 an attractive target for AML treatment. To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies. Among these derivatives, MY-10 exhibited the most potent and selective inhibition of MV4-11 cell proliferation, demonstrating potent inhibitory activity against FLT3-ITD (IC = 6.
View Article and Find Full Text PDFEur J Med Chem
December 2024
Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China. Electronic address:
Targeting XPO1 inhibition has emerged as a promising therapeutic strategy in cancer treatment. Despite the numerous XPO1 inhibitors reported to date, no XPO1 degraders have been disclosed. In this study, we reported the design, synthesis and biological characterization of small-molecule XPO1 degraders based upon the proteolysis targeting chimera (PROTAC), marking the first public disclosure of XPO1 degraders.
View Article and Find Full Text PDFLeuk Res
December 2024
Endocrinology Department, The Third People's Hospital of Henan Province, China. Electronic address:
Objective: The primary methods for defining the prognostic risk of AML patients are cytogenetic and molecular analysis at the time of diagnosis. However, the prognosis of intermediate-risk patients is still not well assessed for biomarkers. The main objective of this meta-analysis is to evaluate the relationship between circRNAs and AML prognosis, to provide a theoretical basis for finding effective prognostic indicators in intermediate-risk patients, and to provide an important scientific basis for the development or revision of WHO practice guidelines and ELN risk classification, and to highlight the importance of continuing to focus on and evaluate the prognostic impact of circRNAs on AML in future studies.
View Article and Find Full Text PDFCell Mol Biol (Noisy-le-grand)
November 2024
Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Türkiye.
Homeobox (HOX) transcript antisense RNA (HOTAIR) and HOX genes are reported to be more expressed in various cancers in humans in recent studies. The role of HOTAIR and HOXD genes in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) is not well known. In this study, expression levels of HOXD8, HOXD9 and HOXD11 from HOXD gene family and HOTAIR were determined from peripheral blood samples of 30 AML and 30 CML patients and 20 healthy volunteers by quantitative Real Time PCR.
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