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.

We thank Melin Khandekar for the discussion and critical reading of the manuscript. We also thank Yuko Kikuchi, Naomi Kaneko, and Reiko Kawai for help.

This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture (Advanced Research for Cancer and General Area) to R.S. and M.Y., from JST ERATO and the Naito Foundation to M.Y., and from the Dutch Organization for Scientific Research NWO and the Dutch Cancer Society KWF to S.P.