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

ABSTRACT: Precision medicine can significantly improve outcomes for patients with cancer, 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 but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term 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 with cells with monoallelic mutations. 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 patients with cancer.

SUBMITTER: Stolzel F

PROVIDER: S-EPMC9977313 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Stölzel Friedrich F Fordham Sarah E SE Nandana Devi D Lin Wei-Yu WY Blair Helen H Elstob Claire C Bell Hayden L HL Mohr Brigitte B Ruhnke Leo L Kunadt Desiree D Dill Claudia C Allsop Daniel D Piddock Rachel R Soura Emmanouela-Niki EN Park Catherine C Fadly Mohd M Rahman Thahira T Alharbi Abrar A Wobus Manja M Altmann Heidi H Röllig Christoph C Wagenführ Lisa L Jones Gail L GL Menne Tobias T Jackson Graham H GH Marr Helen J HJ Fitzgibbon Jude J Onel Kenan K Meggendorfer Manja M Robinson Amber A Bziuk Zuzanna Z Bowes Emily E Heidenreich Olaf O Haferlach Torsten T Villar Sara S Ariceta Beñat B Diaz Rosa Ayala RA Altschuler Steven J SJ Wu Lani F LF Prosper Felipe F Montesinos Pau P Martinez-Lopez Joaquin J Bornhäuser Martin M Allan James M JM

JCI insight 20230124 2

Precision medicine can significantly improve outcomes for patients with cancer, 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 but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. ...[more]

PMID: 36480300

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Project description:BackgroundThe tet oncogene family member 2 (TET2) gene has been reported to be involved in DNA methylation and epigenetic regulation in acute myeloid leukemia (AML). Various studies have proven functional role of TET2 mutations in AML. We herein studied the frequency and genotype-phenotype correlation of TET2 gene in AML patients in Sindh, Pakistan.Patients and methodsThe current study was carried out at Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan, in collaboration with National Institute of Blood Disease & Bone Marrow Transplant, Karachi, Pakistan, during the period from June 2019 to June 2020. A total of 130 patients diagnosed with AML were screened for TET2 mutations. Whole exome sequencing of 14 individuals was carried out to find the genetic variants in TET2 gene. The pathogenicity of the variants was predicted by SIFT, PolyPhen2, Mutation Taster and CADD Phred scores. The allele frequency of the variants was compared with global population using 1000 genomes project and Exome Aggregation Consortium (ExAC). Furthermore, exon 3 and exon 5 of the TET2 gene were sequenced by using Sanger sequencing. The findings were correlated with subtypes of AML and corresponding karyotypes.ResultsThrough the exome sequencing, 17 genetic variants (13 SNPs and four indels) were identified in 14 individuals. Of these, four variants that is, one frameshift deletion, one frameshift insertion and two nonsense variants were novel and not present in dbSNP151 database. Three novel variants were found in exon 3 including two frameshift variants that is, p.T395fs and G494fs, predicted as deleterious by CADD Phred scores, and one stop-gain variant (p.G898X) predicted as deleterious by Mutation Taster and CADD Phred scores. One novel non sense variant (p.Q1191X) was found in the exon 5 predicted as deleterious by SIFT, Mutation Taster and CADD Phred scores. Sanger sequencing analysis revealed one novel deletion at g105233851: del.TAGATAGA, and one novel SNP g;105233861 T>G identified in the TET2 gene. Majority of the exon 3 mutations were seen in the patients diagnosed with AML with maturation, and had a normal karyotype.ConclusionTET2 mutations were identified in around 16% of the total patients of our study indicating other mechanisms being involved in pathophysiology of AML in this cohort. The TET2 mutations provide a prognostic value in determining AML classification.

Dataset Information

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

Publications

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

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