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Persistent Transactivation by Meis1 Replaces Hox Function in Myeloid Leukemogenesis Models: Evidence for Co-Occupancy of Meis1-Pbx and Hox-Pbx Complexes on Promoters of Leukemia-Associated Genes

2006; Taylor & Francis; Volume: 26; Issue: 10 Linguagem: Inglês

10.1128/mcb.26.10.3902-3916.2006

1098-5549

Gang Greg Wang, Martina P. Pasillas, Mark P. Kamps,

Invertebrate Immune Response Mechanisms

Homeobox transcription factors Meis1 and Hoxa9 promote hematopoietic progenitor self-renewal and cooperate to cause acute myeloid leukemia (AML). While Hoxa9 alone blocks the differentiation of nonleukemogenic myeloid cell-committed progenitors, coexpression withMeis1 is required for the production of AMLinitiating progenitors, which also transcribe a group of hematopoietic stem cell genes, including Cd34 and Flt3 (defined as Meis1-related leukemic signature genes).Here, we use dominant trans-activating (Vp16 fusion) or trans-repressing (engrailed fusion) forms of Meis1 to define its biochemical functions that contribute to leukemogenesis.Surprisingly, Vp16-Meis1 (but not engrailed-Meis1) functioned as an autonomous oncoprotein that mimicked combined activities of Meis1 plus Hoxa9, immortalizing early progenitors, inducing low-level expression of Meis1-related signature genes, and causing leukemia without coexpression of exogenous or endogenous Hox genes.Vp16-Meis1-mediated transformation required the Meis1 function of binding to Pbx and DNA but not its C-terminal domain (CTD).The absence of endogenous Hox gene expression in Vp16-Meis1-immortalized progenitors allowed us to investigate how Hox alters gene expression and cell biology in early hematopoietic progenitors.Strikingly, expression of Hoxa9 or Hoxa7 stimulated both leukemic aggressiveness and transcription of Meis1-related signature genes in Vp16-Meis1 progenitors.Interestingly, while the Hoxa9 N-terminal domain (NTD) is essential for cooperative transformation with wild-type Meis1, it was dispensable in Vp16-Meis1 progenitors.The fact that a dominant transactivation domain fused to Meis1 replaces the essential functions of both the Meis1 CTD and Hoxa9 NTD suggests that Meis-Pbx and Hox-Pbx (or Hox-Pbx-Meis) complexes co-occupy cellular promoters that drive leukemogenesis and that Meis1 CTD and Hox NTD cooperate in gene activation.Chromatin immunoprecipitation confirmed co-occupancy of Hoxa9 and Meis1 on the Flt3 promoter.Meis1 (myeloid ecotrophic insertion site 1) encodes a homeodomain (HD) transcription factor that positively regulates the expansion and pool size of hematopoietic stem cells (HSCs) and is commandeered in leukemic transformation.Meis1 belongs to the three-amino-acid loop extension family of HD proteins that includes Pbx, which heterodimerizes with Meis1 (9).While Pbx genes are broadly expressed in hematopoiesis, Meis1 expression is high in Sca-I ϩ Lin Ϫ HSCs but down-regulated during transition to Lin ϩ lineages (4, 15, 37).A positive role of Meis1 in HSC expansion is suggested in Meis1 Ϫ/Ϫ mice, which exhibit severe reduction in the number and colony-forming potential of HSCs (4, 15).Hoxa9, which is also expressed specifically in progenitors and required for the expansion and repopulating abilities of HSCs (29, 37, 47), binds both Meis1 and Pbx, suggesting that combinations of Meis-Pbx, Hox-Pbx, and Hox-Pbx-Meis complexes, such as those that regulate Hoxb1 and Hoxb2 expression (16, 21), may also target promoters that control HSC expansion.The functions of Meis, Pbx, and Hox proteins are usurped in leukemogenesis.Originally, Meis1 was discovered as one of