Project Description

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.

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia.
Maroz A, Stachorski L, Emmrich S, Reinhardt K, Xu J, Shao Z, Käbler S, Dertmann T, Hitzler J, Roberts I, Vyas P, Juban G, Hennig C, Hansen G, Li Z, Orkin S, Reinhardt D, Klusmann JH.
Leukemia. 2014 Jan 21;28(6):1259-70. doi: 10.1038/leu.2013.373.

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy.
Stankov MV, El Khatib M, Kumar Thakur B, Heitmann K, Panayotova-Dimitrova D, Schoening J, Bourquin JP, Schweitzer N, Leverkus M, Welte K, Reinhardt D, Li Z, Orkin SH, Behrens GM, Klusmann JH.
Leukemia. 2013 Oct 1;28(3):577-88. doi: 10.1038/leu.2013.264.

Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis.
Klusmann JH, Godinho FJ, Heitmann K, Maroz A, Koch ML, Reinhardt D, Orkin SH, Li Z.
Genes Dev. 2010 Aug 1;24(15):1659-72. doi: 10.1101/gad.1903410.

Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome.
Scheer C, Kratz C, Witt O, Creutzig U, Reinhardt D, Klusmann JH.
Pediatr Blood Cancer. 2016 May 18;63(9):1677-9. doi: 10.1002/pbc.26062.

Therapy reduction in patients with Down Syndrome Myeloid Leukemia: The international ML-DS 2006 trial.
Uffmann M, Rasche M, Zimmermann M, von Neuhoff C, Creutzig U, Dworzak M, Scheffers L, Hasle H, Zwann CM, Reinhardt D, Klusmann JH.
Blood. 2017 Apr 11;pii:blood-2017-01-765057. doi: 10.1182/blood-2017-01-765057.