Bi-allelic TET2 alterations are frequently found in NPM1 mutated AML and constitute a distinct subgroup with unfavorable prognosis

作者：Wencke Walter, Sarah Keppler, Veronika Ecker, Wolfgang Kern, Torsten Haferlach, Anna Stengel · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-339 · 被引用次数：2 · 研究领域：Acute Myeloid Leukemia Research、Protein Degradation and Inhibitors、Myeloproliferative Neoplasms: Diagnosis and Treatment

Abstract Background: Mutations (mut) in TET2 and NPM1 are common in myeloid neoplasms, with NPM1mut defining a distinct genetic entity in acute myeloid leukemia (AML). However, NPM1mut does not always constitute the initiating event and AML-NPM1 represents a heterogeneous group with considerable phenotypic and genetic variability. Generally, AML-NPM1 is associated with a favorable prognosis, especially in the absence of FLT3-ITD. TET2mut, also prevalent in AML, often occurs as an early event in AML development, and double hit (dh) TET2 alterations (alt) are frequently detected. TET2dh is associated with a poor prognosis but, so far, is not part of any genetic AML (sub-) classification. Around 20% of NPM1mut cases also have TET2mut, however, the clonal evolution and cellular origin of these cases remains to be investigated. Aim: Analyzing biallelic TET2alt and concurrent NPM1mut to determine the sequence of genetic events and characterization of these cases. Patients and methods: We characterized 479 patients (pts) with TET2dh and concurrent NPM1mut. Clinical data was available for 290 pts. Cryopreserved cells of 10 pts were processed with the Single-Cell DNA + Protein Sequencing Protocol (MissionBio). 65 pts were analyzed by whole transcriptome sequencing (WTS). 141 AML-NPM1 without TET2dh were used as control cohort (n=51 for overall survival (OS) analysis). Results: Of 3,276 pts diagnosed with AML-NPM1, 479 were found to harbor a TET2dh, accounting for 15% of all AML-NPM1. ...