AbdB-Like Hox Proteins Stabilize DNA Binding by the Meis1 Homeodomain Proteins

Abstract

Recent studies show that Hox homeodomain proteins from paralog groups 1 to 10 gain DNA binding specificity and affinity through cooperative binding with the divergent homeodomain protein Pbx1. However, the AbdB-like Hox proteins from paralogs 11, 12, and 13 do not interact with Pbx1a, raising the possibility of different protein partners. The Meis1 homeobox gene has 44% identity to Pbx within the homeodomain and was identified as a common site of viral integration in myeloid leukemias arising in BXH-2 mice. These integrations result in constitutive activation of Meis1. Furthermore, the Hoxa-9 gene is frequently activated by viral integration in the same BXH-2 leukemias, suggesting a biological synergy between these two distinct classes of homeodomain proteins in causing malignant transformation. We now show that the Hoxa-9 protein physically Although the vertebrate homeobox genes play a critical role in embryonic development (30), there has been little progress in understanding how homeodomain proteins function. Despite the assumption that they are transcription factors (24), few natural regulatory targets have been identified (13, 16), and little data exist showing an in vivo transcriptional role for the mammalian homeodomain proteins. Vertebrate homeobox genes can be divided into the Hox family of clustered genes which contain homeobox sequences related to the Drosophila HOM-C homeobox genes and the numerous subfamilies of non-Hox genes which possess more distantly related homeobox sequences. The 39 Hox genes are arranged in four separate loci (A, B, C, and D), and the genes in different clusters can be aligned on the basis of homology within the homeobox to form so-called paralog groups, which have limited homology with the Drosophila HOM-C genes as well (1). A significant advance in understanding how Hox proteins function has been the demonstration that they form cooperative DNA binding complexes with the non-Hox homeodomain protein Pbx1a (10, 27, 42). We have recently reported that Hox proteins from paralog groups 1 through 10 gain DNA binding specificity through cooperative binding with Pbx1a, but proteins from the remaining three paralog groups, 11, 12, and 13, do not appear to interact with Pbx1a (8, 47). These findings suggest that the Hox proteins from paralog groups 11 through 13 might cooperatively bind to DNA with other non-Hox homeodomain protein partners.In recent studies, we demonstrated that a novel homeobox gene, Meis1, is a common site of viral integration in myeloid leukemias occurring in BXH-2 mice (33). Two forms of the Meis1 transcript, which differ in the amino acid sequence Cterminal to the homeodomain, were identified in all tissues examined (33). The homeodomain of Meis1 has homology with that of Pbx1, and both proteins contain a 3-amino-acid insertion which is a feature of the TALE class of homeobox genes (2). With the exception of the recently described Meisrelated genes (34,48), the N-terminal and C-terminal flanking regions of Meis1 have no homology to known homeodomain proteins. A...

Hox genes in hematopoiesis and leukemogenesis

“…HOX cofactors of the threeamino acid loop extension class have been shown to interact directly with HOX proteins to increase their DNA-binding affinity and specificity and to modify their transregulatory properties (Moens and Selleri, 2006). In general, HOX proteins from paralog groups 1-10 interact physically with PBX1, while those from paralog groups 9-13 interact with MEIS1 (Shen et al, 1997). Thus, loss-of-function mutations of Hox cofactors are predicted to disrupt multiple HOX-dependent pathways.…”

Xmeis1, a protooncogene involved in specifying neural crest cell fate in Xenopus embryos

“…In mammals, while the majority of Hox proteins interact with Pbx (Hox paralogs 1 ± 10) (Chang et al, 1995;Neuteboom et al, 1995;Phelan et al, 1995), only the group 9 and 10 Abd-B class Hox proteins complex with Meis (Shen et al, 1997). Meis, Pbx, and Hox family members have also been reported to form trimeric complexes in vivo (Berthelsen et al, 1998;Swift et al, 1998;Jacobs et al, 1999;Shanmugam et al, 1999;Shen et al, 1999).…”

True

“…11,12 PBX1a, a DNA binding partner of several HOX gene family members, 13 is fused to E2A in acute lymphoblastic leukemia (ALL) containing the t(1;19). 14 Another HOX binding partner, Meis1, 15 is activated by retroviral insertion together with Hoxa7 and Hoxa9 in myeloid leukemia in BXH-2 mice. 16 Finally, MLL, the human homologue of the Drosophila trithorax gene and a positive regulator of HOX gene expression, is expressed in normal human hematopoietic cells and may be required for the proper differentiation of myeloid progenitors.…”