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

Abstract

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 in utero, facilitating the acquisition of additional driver mutations such as truncating GATA1 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, GATA1 mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.

Keywords: ML–DS; TAM; Trisomy 21 (Down syndrome); acute megakaryoblastic leukemia; acute myeloid leukemia; genetic predisposition; transient myeloproliferative disorder of Down syndrome.

Figure 1

Schematic overview of human chromosome 21 (HSA21) and the proposed Down syndrome critical region (DSCR), along with the location of the genes discussed in this article which are suggested to be involved in the dysregulated hematopoiesis observed in individuals with trisomy 21.

Figure 2

Perturbation of fetal liver hematopoiesis caused by trisomy 21 and loss of full length GATA1. (A) In euploid individuals the balanced gene dosages of chromosome 21 and the presence of full length GATA1 contribute to normal fetal liver hematopoiesis. (B) In contrast trisomy 21 causes expansion of hematopoietic stem and progenitor cells (HSPC), megakaryocytic and erythroid cells via increased gene dosages. (C) When an additional GATA1 mutation, which leads to the expression of only the short isoform of GATA1 (GATA1s), is acquired immortalized megakaryocytic blasts rapidly expand at the expense of erythropoiesis. This is known as transient abnormal myelopoiesis which typically originates during fetal liver hematopoiesis.