TP53 loss and TET2 deficiency cooperate to drive lineage-plastic leukemogenesis by transforming progenitors and establishing immune suppressive environment

Loss-of-function mutations of TET2 and TP53 genes are frequently co-observed in AML patients receiving intensive chemotherapy and represent independent predictors for inferior survival in patients after stem cell transplantation. Here we show that TET2 biallelic loss or haploinsufficiency is observed in >10% AML patients with TP53 mutations and associated with poor outcome. In mice, double deletions of TET2 and P53 leads to development of T-ALL, B-ALL or AML and stimulation of pre-leukemic mice via TLR2-TRAF6-A20 axis skews leukemia development toward AML. scRNA-seq of murine blasts reveals that B cell leukemia differentiation is accompanied by transcriptional changes of ll7r and Myb while AML commitment is associated with dynamic elevation of Klf4 and Flt3. Notably, mice with AML exhibit T cell exhaustion, NK dysfunction, and MDSC-like properties which are similarly observed in AML patients with TP53/TET2 co-mutations. Lastly, we demonstrated that silencing of MEK/ERK, JAK/STAT or TLR-A20 signaling pathways, that are overexpressed in TP53/TET2-mutant AML, restores normal differentiation in vitro and in vivo. Collectively, these findings provide evidence that TP53 deficiency and TET2 loss cooperate to transform hematopoietic progenitors and play a role in AML development and identify novel targets to deliver therapy for this high-risk AML group. Overall design: 16 samples are provided. Genotypes are WT, TP53-/- and TET2-/-TP53-/-. Animals with primary disease and recipients of transplanted tissues are included. Tissues analyzed include spleen and marrow. All samples were processed using 10X Genomics 3' capture scRNA-seq technology.