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

Autor: Gabriel Gracia-Maldonado, James C. Mulloy, Bruce J. Aronow, Ashish R Kumar, Mark Wunderlich, Kevin A. Link, Nupur Dasgupta, Jayeeta Roychoudhury, Zeenath Unnisa, Gang Huang, Jason Clark
Rok vydání: 2015
Předmět:
Oncogene Proteins
Fusion
Blotting
Western
Immunology
Apoptosis
Mice
Transgenic
Leukemia inhibitory factor receptor
Biology
Biochemistry
Oxidative Phosphorylation
Cell Line
Fusion gene
Downregulation and upregulation
Cell Line
Tumor
hemic and lymphatic diseases
medicine
Animals
Humans
Myeloid Ecotropic Viral Integration Site 1 Protein
Cell Proliferation
Oligonucleotide Array Sequence Analysis
Homeodomain Proteins
Mice
Knockout
Regulation of gene expression
Leukemia
Myeloid Neoplasia
Dichloroacetic Acid
Gene Expression Regulation
Leukemic
HEK 293 cells
Cell Biology
Hematology
medicine.disease
Cell Hypoxia
Hepatic Leukemia Factor
Neoplasm Proteins
Oxidative Stress
Basic-Leucine Zipper Transcription Factors
HEK293 Cells
Cancer research
RNA Interference
Reactive Oxygen Species
Transcriptome
Chromatin immunoprecipitation
Myeloid-Lymphoid Leukemia Protein
Zdroj: Blood. 125:2544-2552
ISSN: 1528-0020
0006-4971
Popis: 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.
Databáze: OpenAIRE
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