AUTHOR=Grimm Juliane , Heckl Dirk , Klusmann Jan-Henning 

TITLE=Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.636633

DOI=10.3389/fonc.2021.636633

ISSN=2234-943X

ABSTRACT=<p>Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML–DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting <italic>in utero</italic>, facilitating the acquisition of additional driver mutations such as truncating <italic>GATA1</italic> variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)—a pre-leukemic state preceding the progression to ML–DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, <italic>GATA1</italic> mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.</p>