The Influence of Methylating Mutations on Acute Myeloid Leukemia: Preliminary Analysis on 56 Patients

Abstract

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by abnormal proliferation and a lack of differentiation of myeloid blasts. Considering the dismal prognosis this disease presents, several efforts have been made to better classify it and offer a tailored treatment to each subtype. This has been formally done by the World Health Organization (WHO) with the AML classification schemes from 2008 and 2016. Nonetheless, there are still mutations that are not currently included in the WHO AML classification, as in the case of some mutations that influence methylation. In this regard, the present study aimed to determine if some of the mutations that influence DNA methylation can be clustered together regarding methylation, expression, and clinical profile. Data from the TCGA LAML cohort were downloaded via cBioPortal. The analysis was performed using R 3.5.2, and the necessary packages for classical statistics, dimensionality reduction, and machine learning. We included only patients that presented mutations in DNMT3A, TET2, IDH1/2, ASXL1, WT1, and KMT2A. Afterwards, mutations that were present in too few patients were removed from the analysis, thus including a total of 57 AML patients. We observed that regarding expression, methylation, and clinical profile, patients with mutated TET2, IDH1/2, and WT1 presented a high degree of similarity, indicating the equivalence that these mutations present between themselves. Nonetheless, we did not observe this similarity between DNMT3A- and KMT2A-mutated AML. Moreover, when comparing the hypermethylating group with the hypomethylating one, we also observed important differences regarding expression, methylation, and clinical profile. In the current manuscript we offer additional arguments for the similarity of the studied hypermethylating mutations and suggest that those should be clustered together in further classifications. The hypermethylating and hypomethylating groups formed above were shown to be different from each other considering overall survival, methylation profile, expression profile, and clinical characteristics. In this manuscript, we present additional arguments for the similarity of the effect generated by TET2, IDH1/2, and WT1 mutations in AML patients. Thus, we hypothesize that hypermethylating mutations skew the AML cells to a similar phenotype with a possible sensitivity to hypermethylating agents.

TET2/IDH1/2/WT1 and NPM1 Mutations Influence the RUNX1 Expression Correlations in Acute Myeloid Leukemia

“…Moreover, the negatively correlated genes were observed to be linked to myeloid activation. This observation might add another argument to the importance of several genes like TET2/IDH1/2/WT1, NPM1 and RUNX1 in myeloid activation, as we and other groups have shown that the immature phenotype of AML is associated with TET2/IDH1/2/WT1 mutations [2,3]. This is also supported by the fact that RUNX1 has been shown to induce the expression of IL3 and SPI1, which are known for their importance in myeloid differentiation [15].…”

“…Of the mutations that have been shown to be important in AML biology, of particular interest are mutations in TET2, IDH1, IDH2 and WT1, as they are known to influence both the epigenetic and transcriptomic landscape of AML [2]. These mutations are considered as having similar effects regarding the methylation changes, transcriptomic profile and immature phenotype they induce.…”

“…We, as well as other authors, have shown that, in the case of AML, these mutations have a similar methylation and transcription profile and are associated with more immature forms of AML. Because of this, it can be proposed that these mutations may influence the maturity of AML blasts and potentially form a separate entity of AML [2,6,7].…”

The Potential Equivalents of TET2 Mutations

“…The latter compound (2-hydroxyglutarate) is sterically similar to α-ketoglutarate and acts as a competitive inhibitor to α-ketoglutarate-dependent enzymes [17]. Of those, an important α-ketoglutarate dependent enzyme is TET2, with IDH1/2 mutations being able to mimic the effect of TET2 mutations leading to a similar transcriptomic profile as we have previously shown [18].…”

“…effect to that of TET2 mutation [39]. More than this, we have shown that mutations in WT1 are associated with similar methylation and transcriptomic profiles to that of TET2/IDH1/2 mutations in the case of AML [18]. In the same article, we proposed that TET2/IDH1/2/WT1 mutated AML to be considered as being similar to each other.…”