Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.
Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.
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DOI：
10.1016/j.cell.2016.08.057
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发表时间：
2016-09-22
期刊：
影响因子：
64.5
通讯作者：
Scadden DT
中科院分区：
文献类型：
--
作者：
Sykes DB;Kfoury YS;Mercier FE;Wawer MJ;Law JM;Haynes MK;Lewis TA;Schajnovitz A;Jain E;Lee D;Meyer H;Pierce KA;Tolliday NJ;Waller A;Ferrara SJ;Eheim AL;Stoeckigt D;Maxcy KL;Cobert JM;Bachand J;Szekely BA;Mukherjee S;Sklar LA;Kotz JD;Clish CB;Sadreyev RI;Clemons PA;Janzer A;Schreiber SL;Scadden DT
While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML. Inhibition of a metabolic enzyme involved in pyrimidine biosynthesis induces differentiation of leukemic cells, identifying a potential therapeutic approach for treating a range of acute myeloid leukemias, independent of their oncogenic driver.
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影响因子：
5.2
作者：
Jóźwiak P;Forma E;Bryś M;Krześlak A
通讯作者：
Krześlak A
影响因子：
8
作者：
Collins CT;Hess JL
通讯作者：
Hess JL
DOI：
10.1083/jcb.201501101
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bond MR;Hanover JA
通讯作者：
Hanover JA
影响因子：
4.3
作者：
Loffler, M;Jockel, J;Becker, C
通讯作者：
Becker, C
影响因子：
4.8
作者：
Doscas, Michelle E.;Williamson, Ashley J.;Usha, Lydia;Bogachkov, Yedida;Rao, Geetha S.;Xiao, Fei;Wang, Yimin;Ruby, Carl;Kaufman, Howard;Zhou, Jingsong;Williams, James W.;Li, Yi;Xu, Xiulong
通讯作者：
Xu, Xiulong