High-Fat Diet Promotes Acute Promyelocytic Leukemia through PPARδ-Enhanced Self-renewal of Preleukemic Progenitors

Author:

Mazzarella Luca1ORCID,Falvo Paolo1ORCID,Adinolfi Marta1ORCID,Tini Giulia1ORCID,Gatti Elena1ORCID,Piccioni Rossana1ORCID,Bonetti Emanuele1ORCID,Gavilán Elena1ORCID,Valli Debora1ORCID,Gruszka Alicja1ORCID,Bodini Margherita1ORCID,Gallo Barbara1ORCID,Orecchioni Stefania1ORCID,de Michele Giulia1ORCID,Migliaccio Enrica1ORCID,Duso Bruno A.1ORCID,Roerink Sophie2ORCID,Stratton Mike2ORCID,Bertolini Francesco1ORCID,Alcalay Myriam13ORCID,Dellino Gaetano Ivan13ORCID,Pelicci Pier Giuseppe13ORCID

Affiliation:

1. 1IRCCS European Institute of Oncology, Milan, Italy.

2. 2Wellcome Trust Sanger Institute, Cambridge, United Kingdom.

3. 3Department of Oncology and Hemato-Oncology, University of Milan.

Abstract

Abstract Risk and outcome of acute promyelocytic leukemia (APL) are particularly worsened in obese-overweight individuals, but the underlying molecular mechanism is unknown. In established mouse APL models (Ctsg-PML::RARA), we confirmed that obesity induced by high-fat diet (HFD) enhances leukemogenesis by increasing penetrance and shortening latency, providing an ideal model to investigate obesity-induced molecular events in the preleukemic phase. Surprisingly, despite increasing DNA damage in hematopoietic stem cells (HSC), HFD only minimally increased mutational load, with no relevant impact on known cancer-driving genes. HFD expanded and enhanced self-renewal of hematopoietic progenitor cells (HPC), with concomitant reduction in long-term HSCs. Importantly, linoleic acid, abundant in HFD, fully recapitulates the effect of HFD on the self-renewal of PML::RARA HPCs through activation of peroxisome proliferator-activated receptor delta, a central regulator of fatty acid metabolism. Our findings inform dietary/pharmacologic interventions to counteract obesity-associated cancers and suggest that nongenetic factors play a key role. Prevention Relevance: Our work informs interventions aimed at counteracting the cancer-promoting effect of obesity. On the basis of our study, individuals with a history of chronic obesity may still significantly reduce their risk by switching to a healthier lifestyle, a concept supported by evidence in solid tumors but not yet in hematologic malignancies. See related Spotlight, p. 47

Funder

Fondazione AIRC per la ricerca sul cancro ETS

Ministero della Salute

European Hematology Association

European Research Council

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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