Obesity-Driven Acceleration of Acute Promyelocytic Leukemia Development in Mice with Inserted PML-RARa

While a number of solid tumors are identified as obesity-associated cancers, multiple myeloma and acute promyelocytic leukemia (APL) are the only hematologic malignancies included in this category. APL is a highly treatable form of AML characterized by maturation arrest at the promyelocyte stage, and frequent cures with combined ATRA and Arsenic Trioxide therapy. APL is initiated by a chromosomal translocation that causes the fusion of thePMLandRARAgenes, leading to the production of PML-RARA protein. To determine if obesity accelerates the development of APL, we used a genetically-engineered knock-in model in which human PML-RARA cDNA was inserted into the 5' untranslated region of the murine cathepsin G gene (Ctsg), which targets expression to early myeloid progenitor cells. This knock-in transgene was extensively backcrossed (>20 generations) into the C57BL/6J (B6) genetic background, which has been consistently shown to render mice susceptible to diet-induced obesity.Ctsg-PML-RARA mice developed on the B6 background generate a lethal APL-like leukemia with a latency of 8-12 months, and a penetrance of about 60%, as cooperating mutations occur and cause clinical disease.

We placed cohorts of B6.Ctsg-PML-RARA heterozygous (mCG^+/PR) and wild-type (WT) mice, genotyped by PCR, on high-fat (HFD) [57% coconut oil fat] and low-fat (LFD) [10% coconut oil fat] diets, collecting peripheral blood via the retro- orbital sinus at 30 day intervals and performing automated blood counts to observe temporal associations in disease development. HFD feeding significantly accelerated the development of APL in mCG^+/PR mice, leading to anemia, thrombocytopenia, leukocytosis of the granulocyte series, and splenomegaly. Survival rate reduction demonstrated sexual-dimorphism, with male HFD-fed mCG^+/PR mice displaying a median leukemia-free survival time of 211 days compared to 266 days in the female HFD-fed mCG^+/PR cohort. In contrast, LFD-fed mCG^+/PR male mice showed a median survival time of 318 days, whereas none of LFD-fed mCG^+/PR female group nor any of the WT groups on HFD or LFD have reached median survival as of 325 days. Moreover, no signs of leukemia were observed in either HFD- and LFD-fed WT groups, indicating that adiposity alone had no leukemogenic effect. These studies clearly demonstrate that obesity accelerates leukemogenesis in theCtsg-PML-RARA mouse model of acute promyelocytic leukemia.

High density flow cytometry will be applied in the bone marrow of the different groups to evaluate the modulation of multiple hematopoietic cell lineages and cell surface markers.