Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Genetic Predisposition to Disease* ; Metabolic Networks and Pathways* ; Polymorphism, Single Nucleotide*; Biomarkers/*analysis ; Computational Biology/*methods ; Diabetes Mellitus, Type 2/*pathology ; Leukemia, Myeloid, Acute/*pathology; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Genome-Wide Association Study ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism

Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG , rs11108094 on USP44 , rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44 , METAP2 , PPARG , TIMP4 and RPS6KA1 , in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI 3 K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML.

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Keywords: acute myeloid leukemia (AML); metabolic pathways; single-nucleotide polymorphisms (SNPs); type-2 diabetes mellitus (T2D)

0 (Biomarkers)

Date Created: 20210910 Date Completed: 20211018 Latest Revision: 20211018

20221213

PMC8431701

10.3390/ijms22179322

34502231