Djamai Hanane, Berrou Jeannig, Dupont Mélanie, Coudé Marie-Magdelaine, Delord Marc, Clappier Emmanuelle, Marceau-Renaut Alice, Kaci Anna, Raffoux Emmanuel, Itzykson Raphaël, Berthier Caroline, Wu Hsin-Chieh, Hleihel Rita, Bazarbachi Ali, de Thé Hugues, Baruchel André, Gardin Claude, Dombret Hervé, Braun Thorsten
Laboratoire de Transfert des Leucémies, URP-3518, Institut de Recherche Saint Louis, Université de Paris, 75010 Paris, France.
Laboratory of Hematology, Hôpital Saint-Louis, AP-HP, Université de Paris, 75010 Paris, France.
Biomedicines. 2021 Nov 17;9(11):1704. doi: 10.3390/biomedicines9111704.
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.
包括OTX015（MK-8628）和JQ1在内的溴结构域和额外末端结构域（BET）抑制剂对包括急性髓系白血病（AML）细胞在内的细胞显示出抗白血病活性。然而，BET抑制剂在AML中的生物学效应尚未得到充分研究。即使预后较好的AML患者也可能复发，治疗仍然困难。全反式维甲酸（ATRA）联合三氧化二砷（ATO）的分化疗法在AML中显示出活性。我们发现，BET抑制剂与ATO+ATRA类似，可诱导OCI-AML3细胞系和原代细胞发生分化和凋亡，且二者相互独立。此外，BET抑制剂可诱导蛋白酶体依赖性的核仁磷酸蛋白1（NPM1）c降解。BET抑制剂在细胞质中降解NPM1c，而含溴结构域蛋白4（BRD4）在细胞核中降解，这表明恢复细胞核中NPM1/BRD4的平衡对BET抑制剂的疗效至关重要。虽然ATO+ATRA在IMS-M2细胞系中具有显著的生物学活性，但这些细胞对BET抑制剂耐药。基因谱分析显示，IMS-M2细胞可能通过上调白血病干细胞（LSC）途径来抵抗BET抑制剂，而与核心BET反应性转录程序的下调无关。ATO+ATRA可下调特定的基因特征，而BET抑制剂的抗白血病作用似乎与基因无关。我们的临床前研究结果鼓励对AML患者进行BET抑制剂的临床试验。
