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GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

ABSTRACT: Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1-mutations (GATA1s). Here we analyzed the effect of on gene expression upon ectopic expression of Gata1s or Gata1, while simultaneously knocking down endogenous GATA1, in wild-type CD34+-hematopoietic stem and progenitor cells during myeloid differentiation. Ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. While GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. We lentivirally transduced wild-type CD34+-hematopoietic stem and progenitor cells to ectopically express Gata1s or Gata1, while simultaneously knocking down endogenous GATA1, and cultured them in myeloid differentiation for 0, 4 and 14 days.

ORGANISM(S): Homo sapiens

SUBMITTER: Jan-Henning Klusmann 

PROVIDER: E-GEOD-56332 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia.

Maroz A A   Stachorski L L   Emmrich S S   Reinhardt K K   Xu J J   Shao Z Z   Käbler S S   Dertmann T T   Hitzler J J   Roberts I I   Vyas P P   Juban G G   Hennig C C   Hansen G G   Li Z Z   Orkin S S   Reinhardt D D   Klusmann J-H JH  

Leukemia 20131213 6

Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1 mutations (GATA1s). Here we report that TL-cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s mutations as sorted TL blasts, consistent with their clonal origin. TL blasts exhibited a genetic program characteristic of eosinophils and differentiated along t  ...[more]

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