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

• Published in: Blood Vol. 139; no. 21; pp. 3159 - 3165
• Main Authors: Hasle, Henrik, Kline, Ronald M., Kjeldsen, Eigil, Nik-Abdul-Rashid, Nik F., Bhojwani, Deepa, Verboon, Jeffrey M., DiTroia, Stephanie P., Chao, Katherine R., Raaschou-Jensen, Klas, Palle, Josefine, Zwaan, C. Michel, Nyvold, Charlotte Guldborg, Sankaran, Vijay G., Cantor, Alan B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26-05-2022; American Society of Hematology
• Subjects: Child, Preschool; Down Syndrome - complications; Down Syndrome - genetics; GATA1 Transcription Factor - genetics; Germ-Line Mutation; Humans; Leukemia, Megakaryoblastic, Acute - complications; Leukemia, Megakaryoblastic, Acute - genetics; Leukemia, Myeloid - complications; Male; Mutation; Myeloid Neoplasia; Phenotype; Trisomy
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021011463

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.
•GATA1s-generating mutations and trisomy 21 in either order results in a megakaryoblastic leukemia similar to myeloid leukemia of Down syndrome.•Germline GATA1s-generating mutations are associated with familial predisposition for leukemia and myelodysplastic syndrome.
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