Abstract
Meis1 is recognized as an important transcriptional regulator in hematopoietic development and is strongly implicated in the pathogenesis of leukemia, both as a Hox transcription factor co-factor and independently. Despite the emerging recognition of Meis1’s importance in the context of both normal and leukemic hematopoiesis, there is not yet a full understanding of Meis1’s functions and the relevant pathways and genes mediating its functions. Recently, several conditional mouse models for Meis1 have been established. These models highlight a critical role for Meis1 in adult mouse hematopoietic stem cells (HSCs) and implicate reactive oxygen species (ROS) as a mediator of Meis1 function in this compartment. There are, however, several reported differences between these studies in terms of downstream progenitor populations impacted and effectors of function. In this study, we describe further characterization of a conditional knockout model based on mice carrying a loxP-flanked exon 8 of Meis1 which we crossed onto the inducible Cre localization/expression strains, B6;129-Gt(ROSA)26Sortm1(Cre/ERT)Nat/J or B6.Cg-Tg(Mx1-Cre)1Cgn/J. Findings obtained from these two inducible Meis1 knockout models confirm and extend previous reports of the essential role of Meis1 in adult HSC maintenance and expansion and provide new evidence that highlights key roles of Meis1 in both megakaryopoiesis and erythropoiesis. Gene expression analyses point to a number of candidate genes involved in Meis1’s role in hematopoiesis. Our data additionally support recent evidence of a role of Meis1 in ROS regulation.
Highlights
Myeloid ecotropic virus insertion site 1 (Meis1) was first described in 1995 as a common viral integration site in the BXH-2 murine model of myeloid leukemogenesis [1]
Mice from both strains were born in expected numbers and appropriate frequencies, suggesting that there was no selection against untreated MxCre/Meis1fl/fl or ERTCre/Meis1fl/fl germ cells or embryos in vivo
In a serial transplantation assay we show that Meis1-/- hematopoietic stem cells (HSCs) are almost devoid of self-renewal capacity as they fail to contribute to hematopoietic reconstitution in secondary recipients
Summary
Myeloid ecotropic virus insertion site 1 (Meis1) was first described in 1995 as a common viral integration site in the BXH-2 murine model of myeloid leukemogenesis [1]. Meis has attracted interest by virtue of its intimate association with Hox genes in the development of leukemia in mouse models and frequent co-expression with HOX genes in human acute myeloid leukemia samples [1,2,3]. As a Hox co-factor, Meis confers specificity to Hox. PLOS ONE | DOI:10.1371/journal.pone.0151584. Meis in Hematopoiesis role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Bioinfo did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the 'author contributions' section
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