Abstract

Two types of GATA1-related leukemias have been noticed. One is the erythroid leukemia develops in mice as a consequence of deficient expression of GATA1, while the other is acute megakaryoblastic leukemia (AMKL) that arises in Down syndrome (DS) children as a consequence of somatic N-terminally truncation (ΔNT) mutation of GATA1 (reviewed in Shimizu et al, Nat Rev Cancer 2008). We hypothesized that modeling of the human mutation in mice might provide novel insights into human TMD and DS-AMKL, since the GATA1 N-terminal (NT) function is apparently important in these disorders. A previous report showed that immature megakaryocytic progenitors in the yolk sac and early fetal liver of knock-in mice that expressed a mutant GATA1 protein lacking amino acids 3 to 63 (and not 1–83, as in the DS-associated AKML patients) developed a hyperproliferative phenotype, but also that these aberrant cells disappeared from fetal blood by E14.5. The same phenotype was detected in conditional knockout mice in which Gata1 exon 2 (which encodes the wild-type start codon) was deleted. Since this phenotype was substantially different from human TMD, the contribution of the GATA1 NT 83 amino acids to human TMD pathogenesis remained obscure. Therefore, we adopted a transgenic complementation/rescue approach to more directly analyze NT domain function. We generated mice that were rescued from GATA1-deficient lethality by transgenic expression of a GATA1 mutant lacking the N-terminal 83 amino acids, a protein that is identical to the mutant GATA1 factor encountered in human TMD and DS-AKML cases. We discovered that expression of this shortened GATA1 protein in mice phenocopies human TMD in DS children preceding AMKL; immature megakaryocytes accumulate massively in the perinatal livers of mutant mice. However, unlike the usual disease progression in humans, these mouse mutants never develop leukemia. These results unequivocally revealed that expression of the short form of GATA1 is sufficient to induce hyperproliferative fetal megakaryopoiesis, but additional mutation(s) to the GATA1/Gata1 N-terminal deletion is necessary to transform those hyperproliferative megakaryocytic cells into overt leukemic cells in both mouse and human. Thus, this model significantly clarifies our understanding of the distinct molecular mechanisms by which the GATA1 protein can contribute to the multi-step leukemogenesis.

Disclosures: No relevant conflicts of interest to declare.

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