GATA1s in Down syndrome AML

Children with Down syndrome (trisomy 21) have a 20-fold greater risk of developing a myeloid leukemia. Approximately 10% of neonates with Down syndrome are diagnosed with transient leukemia, which arises in the fetal liver in utero. In many cases, the leukemia goes into remission soon after birth, likely due to the shift of hematopoiesis from the fetal liver into the bone marrow. However, 30% of these children develop AMKL within three years, due to additional genetic or epigenetic changes.

Nearly all cases of Down syndrome transient leukemia have acquired mutations in GATA1, resulting in a truncated protein called GATA1s. Mutations in GATA1 are sufficient to induce transient leukemia, but only in the presence of a trisomy 21 genetic background. Thus, we are interrogating chromosome 21 for genes that cooperate with GATA1s to drive leukemia development. In addition, we are applying a proteomics approach with mass spectrometry to identify interaction partners of GATA1 and GATA1s.

Finally, whole genome and exome sequencing of Down syndrome patients has yielded unparalleled insights into additional mutations that are acquired during the progression from transient to full-blown leukemia.

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