Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype

Abstract

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.

Graphical abstract

Figure 1.

Identification of GATA1 mutations in affected members of 2 families. (A) Pedigree diagram of families. Arrows indicate index cases. (B) Schematic diagram of normal GATA1 gene splicing and translation and the impact of the c.-21 A>G and c.2 T>C variants. mRNA, messenger RNA; Wt, wild type.

Figure 1.

Identification of GATA1 mutations in affected members of 2 families. (A) Pedigree diagram of families. Arrows indicate index cases. (B) Schematic diagram of normal GATA1 gene splicing and translation and the impact of the c.-21 A>G and c.2 T>C variants. mRNA, messenger RNA; Wt, wild type.

Figure 2.

Similarities between ML-DS and the leukemias that developed in the patients with germline GATA1 c.-21 A>G and c.2 T>C variants. (A) Immunochemical and histochemical characteristics of ML-DS and the patient leukemias. The overlap includes the unique characteristics of ML-DS compared with non-DS myeloid leukemia such as co-expression of myeloid markers (CD13, CD33, and CD38), early progenitor markers (CD34 and CD117), megakaryocytic/erythroid markers (CD41/61, CD42b, CD36, CD71, and CD235a), T-lymphocyte markers (CD4 and CD7), natural killer cell markers (CD56), but absence of monocytic and B-lymphocyte markers. CD7 expression (indicated in bold) is an important marker distinguishing ML-DS from non-DS AMKL. (B) Heat map showing gene expression (using Human Genome U133 Plus 2.0 Array) of samples from diagnostic blood and BM of AMKL in non-DS (3864-5036) and ML-DS (5809-7535) using unsupervised hierarchical clustering. Red, high gene expression; green, low gene expression. Patient IV-2 clusters with most of the ML-DS patients. (C) In vitro drug sensitivity (lethal concentration [LC₅₀]) of the leukemia from family 1 patient IV-2 compared with ML-DS and non-DS myeloid leukemia patients. MPO, myeloperoxidase; p25-p75, 25th – 75th percentile; TdT, terminal deoxynucleotidyl transferase.