Journal Article

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

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

2014

Overview

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 the eosinophil lineage in vitro . Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34 + -hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro . Although 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. Chromatin Immunoprecipitation Sequencing (ChIP-seq) indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1 Δ e2 knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489/1381 / 631/250/2504/223/1468 / 692/699/1541 / 692/699/67/1990/283 / Animals / Apoptosis / Blood diseases / Bone marrow / Cancer Research / CD34 antigen / Cell Differentiation / Cell Proliferation / Cells (biology) / Chromatin / Cloning / Critical Care Medicine / Down syndrome / Down Syndrome - complications / Down Syndrome - genetics / Down Syndrome - pathology / Down's syndrome / E2F protein / Ectopic expression / Eosinophilia / Eosinophilia - etiology / Eosinophilia - pathology / Eosinophils / GATA-1 protein / GATA1 Transcription Factor - genetics / Gene mutations / Genetic aspects / Health aspects / Hematology / Hematopoietic stem cells / Hematopoietic Stem Cells - metabolism / Hematopoietic Stem Cells - pathology / Humans / Immunoprecipitation / Infant / Infant, Newborn / Intensive / Internal Medicine / Leukemia / Leukemia, Myeloid, Acute - complications / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Leukocytes (eosinophilic) / Medical schools / Medicine / Medicine & Public Health / Mice / Mutation / Mutation - genetics / Myc protein / Neonates / Occupancy / Oncology / original-article / Osteoprogenitor cells / Patients / Pediatrics / Phenotypes / Physiological aspects / Precursors / Progenitor cells / Proteins / Real-Time Polymerase Chain Reaction / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / RNA, Messenger - genetics / Transcription / Transcription factors / Tumor Cells, Cultured