American Association for Cancer Research
capr-23-0246_supplementary_figure_s2_suppsf2.pdf (48.89 kB)

Supplementary Figure S2 from High-Fat Diet Promotes Acute Promyelocytic Leukemia through PPARδ-Enhanced Self-renewal of Preleukemic Progenitors

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journal contribution
posted on 2024-02-02, 08:21 authored by Luca Mazzarella, Paolo Falvo, Marta Adinolfi, Giulia Tini, Elena Gatti, Rossana Piccioni, Emanuele Bonetti, Elena Gavilán, Debora Valli, Alicja Gruszka, Margherita Bodini, Barbara Gallo, Stefania Orecchioni, Giulia de Michele, Enrica Migliaccio, Bruno A. Duso, Sophie Roerink, Mike Stratton, Francesco Bertolini, Myriam Alcalay, Gaetano Ivan Dellino, Pier Giuseppe Pelicci

Supplementary Figure S2: extension of RNAseq and PPARd ChIPseq analysis, related to figure 6


Fondazione AIRC per la ricerca sul cancro ETS (AIRC)

Ministero della Salute (Italy Ministry of Health)

European Hematology Association (EHA)

European Research Council (ERC)



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. 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

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