Blockade of miR-150 maturation by MLL-fusion/MYC/LIN-28 is required for MLL-associated leukemia.
Expression of microRNAs (miRNAs) is under stringent regulation at both transcriptional and posttranscriptional levels. Disturbance at either level could cause dysregulation of miRNAs. Here, we show that MLL fusion proteins negatively regulate production of miR-150, an miRNA widely repressed in acute leukemia, by blocking miR-150 precursors from being processed to mature miRNAs through MYC/LIN28 functional axis. Forced expression of miR-150 dramatically inhibited leukemic cell growth and delayed MLL-fusion-mediated leukemogenesis, likely through targeting FLT3 and MYB and thereby interfering with the HOXA9/MEIS1/FLT3/MYB signaling network, which in turn caused downregulation of MYC/LIN28. Collectively, we revealed a MLL-fusion/MYC/LIN28⊣miR-150⊣FLT3/MYB/HOXA9/MEIS1 signaling circuit underlying the pathogenesis of leukemia, where miR-150 functions as a pivotal gatekeeper and its repression is required for leukemogenesis.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Xi
X
Jiang
Hao
H
Huang
Zejuan
Z
Li
Yuanyuan
Y
Li
Xiao
X
Wang
Sandeep
S
Gurbuxani
Ping
P
Chen
Chunjiang
C
He
Dewen
D
You
Shuodan
S
Zhang
Jinhua
J
Wang
Stephen
S
Arnovitz
Abdel
A
Elkahloun
Colles
C
Price
Gia-Ming
GM
Hong
Haomin
H
Ren
Rejani B
RB
Kunjamma
Mary Beth
MB
Neilly
Jonathan M
JM
Matthews
Mengyi
M
Xu
Richard A
RA
Larson
Michelle M
MM
Le Beau
Robert K
RK
Slany
Paul P
PP
Liu
Jun
J
Lu
Jiwang
J
Zhang
Chuan
C
He
Jianjun
J
Chen
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D015536:Down-Regulation; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000209:etiology*; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology*; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins; D035683:MicroRNAs; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D051941:fms-Like Tyrosine Kinase 3; C497422:KMT2A protein, human; C000715187:Lin28A protein, human; C000616391:MEIS1 protein, human; C533097:MIR150, human; C489427:MYC protein, human; C000616392:Meis1 protein, mouse; C489902:Mllt3 protein, mouse; C097899:homeobox protein HOXA9; C497970:FLT3 protein, human