MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia.

Blood
Jayeeta RoychoudhuryAshish R Kumar

Abstract

Leukemias with MLL translocations are often found in infants and are associated with poor outcomes. The pathogenesis of MLL-fusion leukemias has been linked to upregulation of HOX/MEIS1 genes. The functions of the Hox/Meis1 complex in leukemia, however, remain elusive. Here, we used inducible Meis1-knockout mice coupled with MLL-AF9 knockin mice to decipher the mechanistic role of Meis1 in established MLL leukemia. We demonstrate that Meis1 is essential for maintenance of established leukemia. In addition, in both the murine model and human leukemia cells, we found that Meis1 loss led to increased oxidative stress, oxygen flux, and apoptosis. Gene expression and chromatin immunoprecipitation studies revealed hepatic leukemia factor (HLF) as a target gene of Meis1. Hypoxia or HLF expression reversed the oxidative stress, rescuing leukemia development in Meis1-deficient cells. Thus, the leukemia-promoting properties of Meis1 are at least partly mediated by a low-oxidative state, aided by HLF. These results suggest that stimulants of oxidative metabolism could have therapeutic potential in leukemia treatment.

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Citations

May 18, 2016·Experimental Hematology·Ugo TestaElvira Pelosi
Jun 4, 2016·Current Opinion in Hematology·Cailin T Collins, Jay L Hess
Oct 25, 2016·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Shu ChenXiaofang Sheng
Jan 4, 2018·Blood Advances·Ping XiangR Keith Humphries
Jan 27, 2017·Oncoimmunology·Silvio BandiniFederica Cavallo
Mar 31, 2018·Molecular and Clinical Oncology·Jin ZhangWenbin Qian
Aug 27, 2016·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Sai HuangLi Yu

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