High-fat diet promotes Acute Promyelocytic Leukemia through PPARδ-enhanced self-renewal of preleukemic progenitors.
Luca MazzarellaPaolo FalvoMarta AdinolfiGiulia TiniElena GattiRossana PiccioniEmanuele BonettiElena GavilánDebora ValliAlicja M GruszkaMargherita BodiniBarbara GalloStefania OrecchioniGiulia de MicheleEnrica MigliaccioBruno Achutti DusoSophie RoerinkMichael R StrattonFrancesco BertoliniMyriam AlcalayGaetano Ivan DellinoPier Giuseppe PelicciPublished in: Cancer prevention research (Philadelphia, Pa.) (2023)
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 (HSCs), 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 (PPARδ), a central regulator of fatty acid metabolism. Our findings inform dietary/pharmacological interventions to counteract obesity-associated cancers and suggest that nongenetic factors play a key role.
Keyphrases
- high fat diet
- insulin resistance
- adipose tissue
- metabolic syndrome
- weight loss
- high fat diet induced
- bone marrow
- stem cells
- dna damage
- type diabetes
- skeletal muscle
- liver failure
- fatty acid
- drug induced
- respiratory failure
- acute myeloid leukemia
- physical activity
- weight gain
- bariatric surgery
- oxidative stress
- transcription factor
- hepatitis b virus
- mesenchymal stem cells
- genome wide
- squamous cell carcinoma
- gene expression
- cell therapy
- body mass index
- squamous cell
- young adults
- intensive care unit
- obese patients
- lymph node metastasis