The abundance of the short GATA1 isoform affects megakaryocyte differentiation and leukemic predisposition in mice

TL;DR

This study shows that the amount of a specific GATA1 protein variant in mice affects their risk of developing leukemia by influencing megakaryocyte cell maturation.

Contribution

The study reveals that moderate levels of GATA1s promote leukemia, while higher levels prevent it by enabling proper cell differentiation.

Findings

Moderate GATA1s expression in mice leads to a higher risk of developing acute megakaryoblastic leukemia.

Higher GATA1s levels prevent leukemia by promoting proper megakaryocyte differentiation.

Low GATA1s levels result in persistent immature cells, increasing the chance of additional genetic mutations.

Abstract

Transcription factor GATA1 controls the delicate balance between proliferation, differentiation and apoptosis in both the erythroid and megakaryocytic lineages. In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic GATA1 mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome.

The online version contains supplementary material available at 10.1186/s40164-024-00492-9.

1. The abundance of GATA1s is a strong prognostic factor of TMD for leukemia by mediating differentiation of megakaryocytes.

2. Persistent TMD blasts not undergoing differentiation are prone to leukemic transformation.

The online version contains supplementary material available at 10.1186/s40164-024-00492-9.

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