The Erg-onomics of myeloproliferation in Down syndrome.

摘要

Newborns and very young children with Down syndrome (DS) exhibit a spectrum of uncommon myeloid abnormalities including an unusual transient myeloprolifera-tive disorder (TMD) that is observed in less than 10% of DS infants at birth. TMD is characterized by circulating myeloblasts in the peripheral blood and immature megakaryo-blasts infiltrating the fetal liver, bone marrow, and sometimes other tissues. Remarkably, although clonal, in most infants it spontaneously disappears. This condition is preleuke-mic for the 20% to 30% of cases that go on within 1 to 4 years to develop a Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL). Recent observations describe acquired exon 2 mutations in the X-linked GATA1 gene in virtually all DS-associ-ated TMD and AMKL samples analyzed. Identification of the same GATA1 mutations in the cases where DS-AMKL follows TMD in the same patient, but the lack of AMKL progression in most TMD persons, along with important recent observations from a number of laboratories, indicates that the development of DS-AMKL is a multistep and multifacto-rial process. Current models suggest that first, a fetal liver hematopoietic cell trisomic for chromosome 21 may exhibit aberrant hematopoietic progenitor functions. Second, a specific exon 2 GATA1 mutation is acquired, with resultant interaction between chromosome 21 gene product(s) and mutated GATA-1. This provides a selective advantage for these cells, allowing expansion and other behaviors. Finally, acquisition of additional genetic and/or epigenetic events are required for full progression to AMKL. As such, the DS-associated myeloid (and lymphoid) disorders serve as fascinating model(s) of leukemic progression.