Age-specific induction of mutant p53 drives clonal hematopoiesis and acute myeloid leukemia in adult mice

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML versus lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs), collaborates with mutant p53 to predispose towards myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.

Methods
RNA was extracted utilizing the Direct-Zol RNA Microprep kit (Zymo Research, R2060). Barcoded Illumina-compatible stranded total RNA libraries were prepared using the TruSeq Stranded Total RNA kit (Illumina) as previously described. Library pools were quantified by qPCR and sequenced on the HiSeq 4000 sequencer using the 75-bp paired-end format. The raw RNA-seq readouts were subsequently mapped to the mouse mm10 assembly reference genome using TopHat2 and analyzed with DESeq2 (Bioconductor package).