miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia.
MicroRNA (miRNA)-126 is a known regulator of hematopoietic stem cell quiescence. We engineered murine hematopoiesis to express miRNA-126 across all differentiation stages. Thirty percent of mice developed monoclonal B cell leukemia, which was prevented or regressed when a tetracycline-repressible miRNA-126 cassette was switched off. Regression was accompanied by upregulation of cell-cycle regulators and B cell differentiation genes, and downregulation of oncogenic signaling pathways. Expression of dominant-negative p53 delayed blast clearance upon miRNA-126 switch-off, highlighting the relevance of p53 inhibition in miRNA-126 addiction. Forced miRNA-126 expression in mouse and human progenitors reduced p53 transcriptional activity through regulation of multiple p53-related targets. miRNA-126 is highly expressed in a subset of human B-ALL, and antagonizing miRNA-126 in ALL xenograft models triggered apoptosis and reduced disease burden.
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
Silvia
S
Nucera
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
Alice
A
Giustacchini
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
Francesco
F
Boccalatte
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
Andrea
A
Calabria
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
Cristiana
C
Fanciullo
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
Tiziana
T
Plati
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
Anna
A
Ranghetti
Centre for Translational Genomics and Bioinformatics, IRCSS Ospedale San Raffaele, 20132 Milan, Italy.
Jose
J
Garcia-Manteiga
Centre for Translational Genomics and Bioinformatics, IRCSS Ospedale San Raffaele, 20132 Milan, Italy.
Davide
D
Cittaro
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
Fabrizio
F
Benedicenti
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Eric R
ER
Lechman
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
John E
JE
Dick
Vita Salute San Raffaele University, 20132 Milan, Italy; Pathology Unit, IRCSS Ospedale San Raffaele, 20132 Milan, Italy.
Maurilio
M
Ponzoni
Vita Salute San Raffaele University, 20132 Milan, Italy; Hematology and Bone Marrow Transplantation Unit, IRCSS Ospedale San Raffaele, 20132 Milan, Italy.
Fabio
F
Ciceri
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
Eugenio
E
Montini
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy; Hematology and Bone Marrow Transplantation Unit, IRCSS Ospedale San Raffaele, 20132 Milan, Italy. Electronic address: gentner.bernhard@hsr.it.
Bernhard
B
Gentner
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy. Electronic address: naldini.luigi@hsr.it.
Luigi
L
Naldini
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
C527111:MIRN126 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53