<i>TP53</i> mutations confer resistance to hypomethylating agents and BCL-2 inhibition in myeloid neoplasms
Roman R. Schimmer, Larisa V. Kovtonyuk, Nancy Klemm, Jonas Fullin, Sebastian M. Stolz, Jan Mueller, Francisco Caiado, Kari J. Kurppa, Benjamin L. Ebert, Markus G. Manz, Steffen Boettcher
Abstract
TP53 mutations are found in 5% to 10% of patients with de novo acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). TP53 mutations are enriched even further in therapy-related myeloid neoplasms 1,2 because they confer resistance to conventional chemotherapeutics. Consequently, patients with TP53-mutant AML/MDS have inferior response rates and extremely poor survival with standard induction chemotherapy 1,4,5 and even after allogeneic hematopoietic stem cell transplantation. cently, the hypomethylating agents (HMAs) decitabine and azacitidine, with or without the BCL-2 inhibitor venetoclax, have emerged as promising therapeutics for patients with TP53-mutant myeloid neoplasms. 7 However, the various clinical studies testing HMAs, with or without venetoclax, in patients with TP53-mutant AML/MDS have yielded conflicting results 7-18 about whether TP53 mutations are predictive for superior outcomes (summarized in supplemental Table 1), and several preclinical studies suggested that, indeed, TP53 loss increases sensitivity to HMAs. erefore, we set out to clarify the impact of the TP53 mutational status on the response to treatment with HMAs, with or without venetoclax, by taking advantage of recently generated 3 isogenic human AML cell lines harboring the 6 most frequent TP53 missense mutations and null (knockout [KO]) and wildtype (WT) alleles (Figure Unlike xenograft assays with primary AML/MDS patient samples, the isogenic nature of these CRISPR/ Cas9-engineered cell lines allowed us to control for possible genetic confounders.