Abstract
Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of cancers. While some patients respond well to chemotherapy, we describe here a subgroup with distinct molecular features that has very poor prognosis under chemotherapy. The classification of AML relies substantially on cytogenetics, but most cytogenetic abnormalities do not offer targets for development of targeted therapeutics. Therefore, it is important to create a detailed molecular characterization of the subgroup most in need of new targeted therapeutics. Methods: We used a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup. Results: Multi-omics clustering analysis resulted in three primary clusters among 166 AML adult cancer cases in TCGA data. One of these clusters, which we label as the high-risk molecular subgroup (HRMS), consisted of cases that responded very poorly to standard chemotherapy, with only about 10% survival to 2 years. The gene TP53 was mutated in most cases in this subgroup but not in all of them. The top six genes over-expressed in the HRMS subgroup included E2F4, CD34, CD109, MN1, MMLT3, and CD200. Multi-omics pathway analysis using RNA and CNA expression data identified in the HRMS subgroup over-activated pathways related to immune function, cell proliferation, and DNA damage. Conclusion: A distinct subgroup of AML patients are not successfully treated with chemotherapy, and urgently need targeted therapeutics based on the molecular features of this subgroup. Potential drug targets include over-expressed genes E2F4, and MN1, as well as mutations in TP53, and several over-activated molecular pathways.
Highlights
Acute myeloid leukemia (AML) represents one of the most fatal leukemias and ranks among the deadliest of all cancers
From the multiple factorial analysis (MFA) analysis, the first 6 PCs were chosen for unsupervised clustering gene set analysis due to the equal contribution of copy number alteration (CNA) and RNA-seq expression (Figure 1)
The three putative subgroups of cases resulting from our unsupervised clustering analysis (Figure 2) differed from each other both in their prognosis (Figure 3A), with p 2 x 10−8, and in their molecular traits, with ANOVA test false discovery rate (FDR)
Summary
AML represents one of the most fatal leukemias and ranks among the deadliest of all cancers It presents a myriad of chromosomal alterations and gene mutations, comprising a clinically heterogeneous group of diseases (Green and Konig, 2020). Even where cytogenetic aberrations are established and correlated with prognosis, it is important to create a detailed molecular characterization of those subtypes most in need of new targeted therapeutics. We examined multi-omics data to seek intrinsic molecular subgroups that could guide the development of additional effective targeted therapies for patients with poor prognosis under chemotherapy. The classification of AML relies substantially on cytogenetics, but most cytogenetic abnormalities do not offer targets for development of targeted therapeutics. It is important to create a detailed molecular characterization of the subgroup most in need of new targeted therapeutics
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