Dual actions of Meis1 inhibit erythroid progenitor development and sustain general hematopoietic cell proliferation

Abstract

Myeloid ecotropic viral integration site 1 (Meis1) forms a heterodimer with Pbx1 that augments Hox-dependent gene expression and is associated with leukemogenesis and HSC self-renewal. Here we identified 2 independent actions of Meis1 in hematopoietic development: one regulating cellular proliferation and the other involved in megakaryocyte lineage development. First, we found that endogenous IntroductionMeis1 was identified as a common site of proviral integration by the ecotropic virus in BXH-2 mice that promoted myeloid leukemias. 1,2 Meis1 belongs to the TALE class of homeodomain transcription factors characterized by a 3-amino acid loop extension between the ␣-helices within its homeodomain. Meis1 interacts with other homeodomain proteins, 3 in particular Pbx1, 4 forming a heterodimer that recognizes DNA. The Meis1 protein contains a domain that recognizes wild-type Pbx proteins, but not chimeric Pbx1 proteins formed by translocations, such as the E2a-Pbx1 oncoprotein. 5 The Meis1/Pbx dimer cooperatively associates with Hox homeodomain proteins, and in vitro interaction between Meis1, Hoxa9, and Pbx proteins can occur in the absence of DNA. 6 In addition to its Pbx interaction motif, 5 Meis1 also contains a carboxyl-terminal (C-terminal) region that is required for leukemia induction. 7 This C-terminal region of Meis1 contains transcriptional activity regulated by protein kinase A that appears dependent on the coactivator of cAMP response element-binding protein. 8 Thus, Meis1 appears to augment Hox transcription factor activity and can be regulated by extracellular signaling cues.Initial analysis of Meis1 focused on its role in leukemic transformation. Acute myeloid leukemia induced by Hoxa9 was significantly accelerated by coexpression with Meis1, but not by coexpression with Pbx1b. 9 A cellular action of Meis1 appeared to be the suppression of differentiation and the promotion of proliferation in a system of cytokine-driven Hoxa9-immortalized cells. 10 A Hoxa9 chimeric fusion protein, NUP98-Hoxa9, independently induced a silent preleukemic phase of disease, which was accelerated by Meis1, suggesting that Meis1 augments the activities of the Hoxa9-dependent transformational event. 11 Interactions between Meis1 and Hoxa9 also occur in a model of leukemia induced by rearrangements of the MLL/ALL1 gene, which represents approximately 20% of acute lymphoblastic leukemias and 5% to 6% of acute myeloid leukemias. 12 In this setting, Meis1 is an essential, rate-limiting regulator of the development of MLL-dependent leukemias. 12,13 Studies based on Meis1 overexpression initially suggested a role in regulation of proximodistal limb axis development. 14 However, studies based on targeted disruption of Meis1 in mice observed more substantial defects in hematopoiesis, angiogenesis, and eye development. [15][16][17] Complete elimination of Meis1 by gene targeting caused death between embryonic days 11.5 and 14.5. 16 Although definitive myeloerythroid lineages are present in Meis1 Ϫ/Ϫ embryos, the total numbers of co...

MEIS1 regulates early erythroid and megakaryocytic cell fate

“…In this setting, it was found that the expression of Meis1b, which is equivalent to MEIS1D in our study, induced significant skewing of MEP towards the megakaryocytic lineage. 30 This further underlines the stronger transcriptional activity of MEIS1D.…”

“…While the critical role of Meis1 in maintaining quiescence and self-renewal capacity in HSC has been demonstrated earlier, 9,[29][30][31] little is known about the role of this transcription factor in more committed progenitor cells. MEIS1 expression decreases when HSC differentiate to multipotent progenitors, but increases again during megakaryopoiesis.…”

“…While we showed that, in adult human hematopoiesis, MEIS1 exerts its effects at the level of the CMP and GMP, other studies also indicated a role for Meis1 downstream of the CMP in the skewing of MEP towards the megakaryocytic lineage at the expense of erythroid commitment. 30 These differences can be explained in several ways. First, the study by Cai et al was performed in a model system resembling primitive hematopoiesis whereas we investigated adult hematopoiesis.…”

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

“…However, MEIS1 expression is also maintained specifically in the MK lineage [182]. Overexpression studies have shown a MEIS1-driven induction of a MK transcriptional programme [183] and a skewing towards the MK lineage rather than erythroid development [181]. The embryonic lethality and haemorrhages observed in the MEIS1-deficient animals are attributed to a defect in the separation of lymphatic from the blood vessels secondary to a complete lack in the production of platelets [184].…”

“…MEIS1 plays a key role at the stem cell/progenitor stages, promoting appearance of definitive haematopoiesis and cellular self-renewal [180,181]. However, MEIS1 expression is also maintained specifically in the MK lineage [182].…”