MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia.
Enviado por Gabriel Gracia Maldonado el
Título | MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Autores | Roychoudhury, J, Clark, JP, Gracia-Maldonado, G, Unnisa, Z, Wunderlich, M, Link, KA, Dasgupta, N, Aronow, B, Huang, G, Mulloy, JC, Kumar, AR |
Journal | Blood |
Volume | 125 |
Issue | 16 |
Pagination | 2544-52 |
Date Published | 2015 Apr 16 |
ISSN | 1528-0020 |
Palabras clave | Animals, Apoptosis, Basic-Leucine Zipper Transcription Factors, Blotting, Western, Cell Hypoxia, Cell Line, Cell Line, Tumor, Cell Proliferation, Dichloroacetic Acid, Gene Expression Regulation, Leukemic, HEK293 Cells, Homeodomain Proteins, Humans, Leukemia, Mice, Knockout, Mice, Transgenic, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Fusion, Oxidative Phosphorylation, Oxidative Stress, Reactive Oxygen Species, RNA Interference, Transcriptome |
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. |
DOI | 10.1182/blood-2014-09-599258 |
Alternate Journal | Blood |
PubMed ID | 25740828 |
PubMed Central ID | PMC4400291 |
Grant List | P30DK090971 / DK / NIDDK NIH HHS / United States R01 HL111192 / HL / NHLBI NIH HHS / United States R01-HL111192 / HL / NHLBI NIH HHS / United States |