MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia.
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.
Division of Bone Marrow Transplantation and Immune Deficiency.
Jayeeta
J
Roychoudhury
Division of Bone Marrow Transplantation and Immune Deficiency.
Jason P
JP
Clark
Division of Bone Marrow Transplantation and Immune Deficiency.
Gabriel
G
Gracia-Maldonado
Division of Bone Marrow Transplantation and Immune Deficiency.
Zeenath
Z
Unnisa
Division of Experimental Hematology and Cancer Biology.
Mark
M
Wunderlich
Division of Experimental Hematology and Cancer Biology.
Kevin A
KA
Link
Division of Human Genetics, and.
Nupur
N
Dasgupta
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Bruce
B
Aronow
Division of Experimental Hematology and Cancer Biology.
Gang
G
Huang
Division of Experimental Hematology and Cancer Biology.
James C
JC
Mulloy
Division of Bone Marrow Transplantation and Immune Deficiency.
Ashish R
AR
Kumar
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003999:Dichloroacetic Acid / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D059467:Transcriptome
D050976:Basic-Leucine Zipper Transcription Factors; C490670:Hlf protein, mouse; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C474558:MLL-AF9 fusion protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D017382:Reactive Oxygen Species; D051788:Myeloid-Lymphoid Leukemia Protein; D003999:Dichloroacetic Acid