Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice

Danielle C. Shing, Maurizio Trubia, Francesco Marchesi, Enrico Radaelli, Elena Belloni, Cinzia Tapinassi, Eugenio Scanziani, Cristina Mecucci, Barbara Crescenzi, Idoya Lahortiga, Maria D. Odero, Giuseppe Zardo, Alicja Gruszka, Saverio Minucci, Pier Paolo Di Fiore, Pier Giuseppe Pelicci

Research output: Contribution to journalArticlepeer-review


Transgenic expression of the abnormal products of acute myeloid leukemia-associated (AML-associated) primary chromosomal translocations in hematopoietic stem/progenitor cells initiates leukemogenesis in mice, yet additional mutations are needed for leukemia development. We report here aberrant expression of PR domain containing 16 (PRDM16) in AML cells with either translocations of 1p36 or normal karyotype. These carried, respectively, relatively high prevalence of mutations in the TP53 tumor suppressor gene and in the nucleophosmin (NPM) gene, which regulates p53. Two protein isoforms are expressed from PRDM16, which differ in the presence or absence of the PR domain. Overexpression of the short isoform, sPRDM16, in mouse bone marrow induced AML with full penetrance, but only in the absence of p53. The mouse leukemias were characterized by multilineage cellular abnormalities and megakaryocyte dysplasia, a common feature of human AMLs with 1p36 translocations or NPM mutations. Overexpression of sPRDM16 increased the pool of HSCs in vivo, and in vitro blocked myeloid differentiation and prolonged progenitor life span. Loss of p53 augmented the effects of sPRDM16 on stem cell number and induced immortalization of progenitors. Thus, overexpression of sPRDM16 induces abnormal growth of stem cells and progenitors and cooperates with disruption of the p53 pathway in the induction of myeloid leukemia.

Original languageEnglish
Pages (from-to)3696-3707
Number of pages12
JournalJournal of Clinical Investigation
Issue number12
Publication statusPublished - Dec 2007

ASJC Scopus subject areas

  • Medicine(all)


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