PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity.
Acute promyelocitic leukemia (APL) is characterized by the pathognomonic presence in leukemic blasts of the hybrid protein PML/RARA, that acts as a transcriptional repressor impairing the expression of genes that are critical to myeloid differentiation. Here, we show that primary blasts from APL patients express lower levels of the oncosuppressor protein PTEN, as compared to blast cells from other AML subtypes or normal bone marrow, and demonstrate that PML-RARA directly inhibits PTEN expression. We show that All-Trans Retinoic Acid (ATRA) triggers in APL cells an active chromatin status at the core regulatory region of the PTEN promoter, that allows the binding of the myeloid-regulating transcription factor PU.1, and, in turn, the transcriptional induction of PTEN. ATRA, via PML/RARA degradation, also promotes PTEN nuclear re-localization and decreases expression of the PTEN target Aurora A kinase. In conclusion, our findings support the notion that PTEN is one of the primary targets of PML/RARA in APL.
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.|Neuro-Oncohematology Unit, Santa Lucia Foundation, Rome, Italy.
Nélida Inés
NI
Noguera
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.|Neuro-Oncohematology Unit, Santa Lucia Foundation, Rome, Italy.
Maria Liliana
ML
Piredda
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Riccardo
R
Taulli
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
Gianfranco
G
Catalano
Neuro-Oncohematology Unit, Santa Lucia Foundation, Rome, Italy.
Giulia
G
Angelini
Neuro-Oncohematology Unit, Santa Lucia Foundation, Rome, Italy.
Girish
G
Gaur
Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Rome, Italy.
Clara
C
Nervi
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
Maria Teresa
MT
Voso
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Andrea
A
Lunardi
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Pier Paolo
PP
Pandolfi
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.|Neuro-Oncohematology Unit, Santa Lucia Foundation, Rome, Italy.
Francesco
F
Lo-Coco
D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D000099232:Proto-Oncogene Protein Spi-1
D015514:Oncogene Proteins, Fusion; D051059:PTEN Phosphohydrolase; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C494929:PTEN protein, human
PML-RARA; PTEN; PU.1; oncosuppressor