Down syndrome and malignancies: a unique clinical relationship: a paper from the 2008 william beaumont hospital symposium on molecular pathology

Abstract

The patterns of malignancies in Down syndrome (DS) are unique and highlight the relationship between chromosome 21 and cancer. DS children have a approximately 10- to 20-fold higher risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML), as compared with non-DS children, although they do not have a uniformly increased risk of developing solid tumors. DS children with acute lymphoblastic leukemia frequently experience higher levels of treatment-related toxicity and inferior event-free survival rates, as compared with non-DS children. DS children also develop AML with unique features and have a 500-fold increased risk of developing the AML subtype, acute megakaryocytic leukemia (AMkL; M7). Nearly 10% of DS newborns are diagnosed with a variant of AMkL, the transient myeloproliferative disorder, which can resolve spontaneously without treatment; event-free survival rates for DS patients with AMkL ranges from 80% to 100%, in comparison with <30% for non-DS children with AMkL. In addition, somatic mutations of the GATA1 gene have been detected in nearly all DS TMD and AMkL cases and not in leukemia cases in non-DS children. GATA1 mutations are key factors linked to both leukemogenesis and the high cure rates of DS AMkL patients. Identifying the mechanisms that account for the high event-free survival rates of DS AMkL patients may ultimately improve AML treatment as well. Examining leukemogenesis in DS children may identify factors linked to the general development of childhood leukemia and lead to potential new therapeutic strategies to fight this disease.

Figure 1

Schematics illustrating the role of GATA1 mutations in leukemogenesis in DS. The transcription factor gene GATA1 is localized to chromosome Xp11.23. GATA1 encodes a protein (50 kDa) that contains two C4-type zinc fingers, which act in DNA binding and protein-protein interactions, and an N-terminal transcription activation domain. The C-terminal zinc finger binds DNA at the consensus sequence (A/T) GATA (A/G). The N-terminal zinc finger can bind the consensus site GATC and also interacts with the partner protein “friend of GATA1.” This process is essential for normal erythroid and megakaryocytic differentiation. Mutations occurring in exon 2 of the transcription factor gene GATA1 result in the synthesis of a shorter GATA1 protein (40 kDa). The short form of the GATA1 protein (GATA1s) shows similar DNA-binding abilities and interactions with “friend of GATA1”; however, GATA1s exhibits altered transactivation capacity due to the loss of the N-terminal activation domain. The GATA1 mutation is likely an essential factor linked to leukemogenesis in DS; however, it is still not clear if this role is due to the loss of function of the wild-type GATA1 protein or if GATA1s has a unique function in the leukemia progression.