Benjamin Dalyia N, O'Donovan Tracey R, Laursen Kristian B, Orfali Nina, Cahill Mary R, Mongan Nigel P, Gudas Lorraine J, McKenna Sharon L
Cancer Research, University College Cork, Cork, Ireland.
Department of Haematology, Tallaght University Hospital, Dublin, Ireland.
Front Oncol. 2022 Feb 24;12:848517. doi: 10.3389/fonc.2022.848517. eCollection 2022.
Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all--retinoic acid (ATRA) and arsenic trioxide (ATO). Application of differentiation therapy to other AML subtypes would be a major treatment advance. Recent studies have indicated that autophagy plays a key role in the differentiation of ATRA-responsive APL cells. In this study, we have investigated whether differentiation could be enhanced in ATRA resistant cells by promoting autophagy induction with valproic acid (VPA). ATRA sensitive (NB4) and resistant leukemia cells (NB4R and THP-1) were co-treated with ATRA and valproic acid, followed by assessment of autophagy and differentiation. The combination of VPA and ATRA induced autophagic flux and promoted differentiation in ATRA-sensitive and -resistant cell lines. shRNA knockdown of ATG7 and TFEB autophagy regulators impaired both autophagy and differentiation, demonstrating the importance of autophagy in the combination treatment. These data suggest that ATRA combined with valproic acid can promote differentiation in myeloid leukemia cells by mechanism involving autophagy.
急性髓系白血病（AML）是一种侵袭性血癌，总体生存率为30%。急性早幼粒细胞白血病（APL）是AML的一种形式，通过由全反式维甲酸（ATRA）和三氧化二砷（ATO）组成的分化疗法，其治愈率已超过90%。将分化疗法应用于其他AML亚型将是治疗上的一项重大进展。最近的研究表明，自噬在对ATRA有反应的APL细胞分化中起关键作用。在本研究中，我们研究了用丙戊酸（VPA）促进自噬诱导是否能增强ATRA耐药细胞的分化。将对ATRA敏感的（NB4）和耐药的白血病细胞（NB4R和THP-1）与ATRA和丙戊酸共同处理，随后评估自噬和分化情况。VPA和ATRA的联合诱导了自噬通量，并促进了对ATRA敏感和耐药细胞系的分化。对自噬调节因子ATG7和TFEB进行shRNA敲低会损害自噬和分化，这证明了自噬在联合治疗中的重要性。这些数据表明，ATRA与丙戊酸联合可通过涉及自噬的机制促进髓系白血病细胞的分化。
