Truncated BRPF1 Cooperates with Smoothened to Promote Adult Shh Medulloblastoma
Giuseppe Aiello,
Claudio Ballabio,
Riccardo Ruggeri,
Luca Fagnocchi,
Marica Anderle,
Ilaria Morassut,
Davide Caron,
Francesca Garilli,
Francesca Gianno,
Felice Giangaspero,
Silvano Piazza,
Alessandro Romanel,
Alessio Zippo,
Luca Tiberi
Affiliations
Giuseppe Aiello
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Claudio Ballabio
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Riccardo Ruggeri
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Luca Fagnocchi
Laboratory of Chromatin Biology & Epigenetics, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Marica Anderle
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Ilaria Morassut
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Davide Caron
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Francesca Garilli
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Francesca Gianno
Department of Radiologic, Oncologic and Anatomo Pathological Sciences, University Sapienza of Rome, Rome, Italy; IRCCS Neuromed, Pozzilli, Isernia, Italy
Felice Giangaspero
Department of Radiologic, Oncologic and Anatomo Pathological Sciences, University Sapienza of Rome, Rome, Italy; IRCCS Neuromed, Pozzilli, Isernia, Italy
Silvano Piazza
Bioinformatics Core Facility, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Alessandro Romanel
Laboratory of Bioinformatics and Computational Genomics, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Alessio Zippo
Laboratory of Chromatin Biology & Epigenetics, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
Luca Tiberi
Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy; Corresponding author
Summary: The transition of neural progenitors to differentiated postmitotic neurons is mainly considered irreversible in physiological conditions. In the present work, we show that Shh pathway activation through SmoM2 expression promotes postmitotic neurons dedifferentiation, re-entering in the cell cycle and originating medulloblastoma in vivo. Notably, human adult patients present inactivating mutations of the chromatin reader BRPF1 that are associated with SMO mutations and absent in pediatric and adolescent patients. Here, we found that truncated BRPF1 protein, as found in human adult patients, is able to induce medulloblastoma in adult mice upon SmoM2 activation. Indeed, postmitotic neurons re-entered the cell cycle and proliferated as a result of chromatin remodeling of neurons by BRPF1. Our model of brain cancer explains the onset of a subset of human medulloblastoma in adult individuals where granule neuron progenitors are no longer present. : Medulloblastoma is a brain tumor affecting the cerebellum of infants and adults. Aiello et al. establish a mouse model for adult onset, which allows investigation of the pathogenesis of the disease and identifies neurons as putative cells of origin. Keywords: medulloblastoma, dedifferentiation, cell-of-origin, BRPF1, super-enhancers, SHH, adult
