Children with Down syndrome (DS) have a 10-20 fold increased risk of developing leukemia, in particular acute megakaryoblastic leukemia (AMKL). While the genetic lesions that promote leukemia in Down syndrome have been largely undefined, we recently demonstrated that leukemic cells from every DS-AMKL patient examined harbor mutations in the essential hematopoietic transcription factor gene GATA1. In every instance, the mutation involved a small insertion or deletion in GATA1 that resulted in a frame-shift and the introduction of a premature stop codon within the sequences encoding the N-terminal activation domain of GATA-1. These mutations prevent the synthesis of the 50-kD full length GATA-1, but not of a 40-kD isoform initiated further downstream, termed GATA-1s. In this application, we propose to study the mechanism of leukemogenesis in patients with GATA1 mutations. Furthermore, we will seek to identify the cooperating factors that are likely contributed by trisomy 21 in Down syndrome AMKL. Specifically, we plan: 1) To determine the incidence and distribution of GATA1 mutations in a greater number of DS-AMKL samples as well as in DNA from patients with DS pre-leukemia, named Transient Myeloproliferative Disorder; 2) To assess whether loss of GATA-1 in conjunction with the mouse equivalent of trisomy 21 can promote leukemogenesis in mice, and further, whether overexpression of GATA-1s can promote immortalization of GATA-1-deficient megakaryocyte progenitors; and 3) To develop a mouse model of DS-AMKL by creating mice that will conditionally express only the 40-kD isoform of GATA-1 and breeding them to mice with the murine equivalent of DS. Separately, we will also cross these novel GATA1 mutant mice into the BXH-2 strain of mice to identify genes that cooperate with the GATA1 mutations in leukemia. These studies will likely increase our understanding of how GATA1 mutations contribute to the initiation or progression of leukemia in Down syndrome and may also lead to the identification of novel leukemia disease genes on chromosome 21. ? ? ?
Showing the most recent 10 out of 46 publications
