BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including AML cells. Nevertheless, the biological consequences of BETi in AML were not fully investigated. Even if of better prognosis AML patients with may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was independent in the cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a specific gene signature while anti-leukemic effects of BETi appear gene independent. Our preclinical results encourage clinical testing of BETi in AML patients.
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http://dx.doi.org/10.3390/biomedicines9111704 | DOI Listing |
The Acute Promyelocytic Leukemia Asian Consortium analyzed a contemporaneous cohort of newly-diagnosed APL patients treated with and without frontline arsenic trioxide (ATO) in six centers. The objectives were to define the impact of ATO on early deaths and relapses, and its optimal positioning in the overall treatment strategy. In a 21.
View Article and Find Full Text PDFLeuk Res Rep
November 2024
Hematology Laboratory, Central laboratory, Mohammed VI University Hospital, Oujda, Morocco.
Introduction: Acute promyelocytic leukemia (AML-M3), classified as acute Myeloid leukemia with PML RARA according to the 5th edition of the World Health Organization classification of haematolymphoid tumors 2022 [1], is marked by abnormal promyelocyte proliferation and is known for high risks of bleeding and thromboembolic complications. We present a case where lower limb ischemia revealed this leukemia in a child.
Case Report: An 11-year-old with minor ankle trauma developed severe lower limb ischemia, leading to the discovery of subtotal femoral artery thrombosis.
Cancers (Basel)
December 2024
Section of Medical Oncology and Hematology, Department of Internal Medicine, Yale School of Medicine, Yale Comprehensive Cancer Center, New Haven, CT 06510, USA.
The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL), resulting in excellent rates of remission and long-term survival. However, real-world outcomes often fall short of those observed in clinical trials due to various factors related to patient demographics and clinical practices. This review examines APL treatment outcomes in real-world settings and highlights the phenomenon of APL clusters.
View Article and Find Full Text PDFHematology
December 2024
Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Cancer
November 2024
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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