Impact of TET2 mutations On Responsiveness to Demethylating Agents in MDS.
Authors: Jankowska Anna M. , Shaik Mohammed , Cazzolli Heather , Ganetzky Rebecca , Sekeres Mikkael A. , Maciejewski Jaroslaw P. 
Published: October 2019

Abstract
Abstract 1606
Poster Board I-632
Aberrant epigenetic silencing of tumor suppressor and differentiation genes constitutes an important mechanism in the pathogenesis of MDS and related myeloid malignancies. Demethylationg agents such as azacitidine and decitabine lead to degradation of DNMT1 and may reverse aberrant methylation. While the drugs demonstrate efficacy in MDS, response rates are variable. Thus, many primarily refractory patients are exposed to these therapies unnecessarily. While search for markers of responsiveness included study of methylation status of potential marker promoters or global methylation patterns, to date predictive tests have not been developed. Similarly, mechanisms of epigenetic instability responsible for wide-spread promoter methylation have not been clarified, preventing development of diagnostic markers.
TET2 mutations are frequent events in a variety of MDS subtypes, particular chronic myelomonocytic leukemia (CMML) and other MDS/MPN, as well as AML derived from those conditions. It is likely that TET2 alterations are important in the pathogenesis of myeloid malignancies, but little is known regarding the function of TET2. A recent report indicated that a related family member, TET1, converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (hmC). Hydroxylation of 5mC prevents DNMT1 from homologous methylation of daughter DNA strands during cell division, thus preventing maintenance methylation (Tahiliani et al. Nature 324, 2009). Consequently, closely related TET2 may play a role in epigenetic regulation. As a consequence, TET2 mutations may lead to accumulation of aberrantly methylated CpG islands. Of utmost importance is whether TET2 mutations or resultant epigenetic silencing of specific gene or gene groups affects response to hypomethylating agents. We hypothesized that TET2 mutations play a role in epigenetic instability and may serve as markers of responsiveness/refractoriness to the therapy with demethylating agents.
We have determined TET2 mutational status by sequencing all exons in 32 patients with myeloid malignancies (MDS (N=18) and MDS/MPN (N=14)) who underwent therapy with the demethylating agents azacitidine (N=27) or decitabine (N=5). For definition of response we applied International Working Group Criteria in patients who received a sufficient dose and number of cycles to allow assessment of response. Overall response rate (complete+partial responses (CR+PR) + hematologic improvement (HI)) was achieved for 9/32 patients (28%) after 35 cycles, including 4 patients who achieved CR, 2 PR, and 3 CI. In total, 12 TET2 mutations were identified in 9/32 patients (28%), of whom 5 had MDS/MPN (3 with CMML-1/2) and 4 had sAML. Unique compound heterozygosity was found in 3 patients; consequently biallelic inactivation of TET2 was found in 4 patients. For analyses, patients with partial and complete responses were compared with refractory patients and response was correlated with the presence of TET2 mutations. Among TET2-mutated patients, only 1 patient responded to therapy, whereas 8 additional patients, including 3 patients with biallelic inactivation of the TET2 gene, did not show any improvement (11%). In contrast, among patients with WT TET2 gene, responses were seen in 8/23 patients (35%; p=.19). While the cohort of treated patients was small, our preliminary results indicate that the presence of TET2 mutations may represent a negative predictor of response to demethylating agents.

Disclosures
No relevant conflicts of interest to declare.