Genetic and Epigenetic Characterization of a Discordant KMT2A/AFF1-Rearranged Infant Monozygotic Twin Pair.

Alessia Russo,Giovanni Birolo,Lilia Corral,Katia Mareschi,Giuseppe Matullo,Simonetta Guarrera,Luca Trentin,Giovanni Cazzaniga,Clara Viberti,Elisabetta Casalone,Franca Fagioli,Giuseppe Basso

doi:10.3390/ijms22189740

Abstract

The KMT2A/AFF1 rearrangement is associated with an unfavorable prognosis in infant acute lymphocytic leukemia (ALL). Discordant ALL in monozygotic twins is uncommon and represents an attractive resource to evaluate intrauterine environment–genetic interplay in ALL. Mutational and epigenetic profiles were characterized for a discordant KMT2A/AFF1-rearranged infant monozygotic twin pair and their parents, and they were compared to three independent KMT2A/AFF1-positive ALL infants, in which the DNA methylation and gene expression profiles were investigated. A de novo Q61H NRAS mutation was detected in the affected twin at diagnosis and backtracked in both twins at birth. The KMT2A/AFF1 rearrangement was absent at birth in both twins. Genetic analyses conducted at birth gave more insights into the timing of the mutation hit. We identified correlations between DNA methylation and gene expression changes for 32 genes in the three independent affected versus remitted patients. The strongest correlations were observed for the RAB32, PDK4, CXCL3, RANBP17, and MACROD2 genes. This epigenetic signature could be a putative target for the development of novel epigenetic-based therapies and could help in explaining the molecular mechanisms characterizing ALL infants with KMT2A/AFF1 fusions.

Highlights

IntroductionLeukemia in children less than one year old (infants) represents about 3% of all pediatric acute lymphocytic leukemia (ALL) and most frequently develops a B-cell ALL form, which is characterized by an uncontrolled proliferation of immature B-cell precursors in the peripheral blood (PB) and bone marrow [2]
Exome Sequencing on Monozygotic Twins Discordant for acute lymphocytic leukemia (ALL)
To identify ALL-linked de novo somatic mutations, the siblings and parents were subjected to Whole-exome sequencing (WES)

Summary

Introduction

Leukemia in children less than one year old (infants) represents about 3% of all pediatric ALL and most frequently develops a B-cell ALL form, which is characterized by an uncontrolled proliferation of immature B-cell precursors in the peripheral blood (PB) and bone marrow [2]. For children in the first year of life carrying this translocation, leukemia can arise as an aggressive disease with an unfavorable prognosis. It is still under debate whether KMT2A fusions alone are sufficient to cause clinically overt leukemia [2]

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Results

Conclusion