Biallelic TET2 mutations confer sensitivity to 5′-azacitidine in acute myeloid leukemia

Abstract

Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine (Ara-C), but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy resulting in longterm morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared to cells with monoallelic mutation. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.

DNA methylation in T cell leukaemia

“…However, mutations result in reduced levels of functional TET2 whereas silencing by promoter methylation, as seen in T-ALL, causes a complete loss of the protein and can therefore have different consequences. A recent study, for example, showed that only a complete loss of TET2 in the form of bi-allelic lossof-function mutations sensitised AML patients to AZA [410].…”

Resistance of Leukemia Cells to 5-Azacytidine: Different Responses to the Same Induction Protocol

“…These variants presented overexpression of the multidrug efflux pump P-glycoprotein (P-gp) and exhibited resistance to P-gp relative substances in addition to resistance to AZA [10]. Similarly, AZA-resistant variants of HEL cells (a cell line of leukemic erythroblasts) showed increased levels of P-gp expression [11]. Such cells exhibit a multidrug resistance of the P-glycoprotein type and may not have activated specific mechanisms typical for the development of resistance to demethylating agents.…”