Leukemogenesis Caused by Incapacitated GATA-1 Function

Abstract

GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

“…80,81 Similarly, the knockdown of GATA-1 expression to approximately 5% of its wild-type level causes high incidence of erythroleukemia in mice. 87 Therefore the manipulation of either PU.1 or GATA-1 levels produces cellular phenotypic features of blocked differentiation and unlimited proliferation potential. Collectively, the molecular interaction between GATA-1 and PU.1 occurs during early lineage commitment of multi-potential progenitors and enable rapid cell fate choices between the development of leukocytes or red cells from a common progenitor.…”

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

“…The most prominent feature of GATA-1 −/− mice is the embryonic lethality caused by early erythroblast developmental arrest and apoptosis [48]. A knockdown allele expressing 5% of normal GATA-1 levels, in the context of a female heterozygote (in order to bypass embryonic lethality), is associated with development of acute leukemias [49]. These leukemias do not express erythroid markers but rather consist of primitive c-Kit + myeloid cells or of CD19 + B lineage cells.…”

Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles

“…Mutations that reduce GATA-1 activity uncouple survival, proliferation, and differentiation functions of GATA-1. As little as 5% GATA-1 expression protects cells from apoptosis and induces leukemogenesis (36). In humans with Down syndrome, expression of a ''short'' GATA-1 (GATA-1s) lacking amino-terminal sequences is linked to a transient myeloproliferative disorder and acute megakaryoblastic leukemia (37)(38)(39).…”