Acute Megakaryocytic Leukemia

Abstract

Acute megakaryoblastic leukemia (AMKL) is a rare malignancy affecting megakaryocytes, platelet-producing cells that reside in the bone marrow. Children with Down syndrome (DS) are particularly prone to developing the disease and have a different age of onset, distinct genetic mutations, and better prognosis as compared with individuals without DS who develop the disease. Here, we discuss the contributions of chromosome 21 genes and other genetic mutations to AMKL, the clinical features of the disease, and the differing features of DS- and non-DS-AMKL. Further studies elucidating the role of chromosome 21 genes in this disease may aid our understanding of how they function in other types of leukemia, in which they are frequently mutated or differentially expressed. Although researchers have made many insights into understanding AMKL, much more remains to be learned about its underlying molecular mechanisms.

Figure 1.

Genetic events in DS-AMKL. Up to 30% of neonates with Down syndrome (DS) acquire a GATA1 mutation, which leads to exclusive expression of the short Gata1s isoform lacking the first 83 amino acids. Trisomy 21 (T21) and GATA1 mutations are sufficient to initiate transient myeloproliferative disorder (TMD), a preleukemia, but not acute megakaryoblastic leukemia (AMKL), which is accompanied by secondary gene mutations.

Figure 2.

Model of cooperation among trisomy 21 (T21), GATA1 mutations, and cohesin mutations. Trisomy and subsequent overexpression of chromosome 21 genes leads to enhanced self-renewal of GATA1 mutant cells and increased expression of the Gata1s isoform. The addition of loss-of-functional mutations in cohesin complex components further increases expression of chromosome 21 genes as well as GATA1. It also is associated with increased chromatin occupancy of RUNX1 and an altered chromatin accessibility of RUNX, ETS, and GATA binding motifs.