Blood cells are continuously produced throughout life observations, it has been hypothesized that HOX proteins confer positional information along various axes by progenitors organized in a complex developmental and therefore play a role in determining body pattern hierarchy (1). Hematopoietic stem cells have extensive and cell identity. In addition, in vertebrates the physiself-renewal and proliferative capabilities and can give cal order of the genes is reflected also in the temporal rise to mature cells of all hematopoietic lineages. They sequence of their activation. Recently, it has been progenerate pluripotent progenitors that have limited selfposed that temporal colinearity might be accounted for renewal potential but are still capable of differentiating by high order regulatory controls and sharing of regulainto multiple cell types. These precursors in turn give tory elements (14). However, regulation of HOX genes rise to unipotent progenitors committed to differentiate is still poorly understood. There is evidence suggesting along a single lineage. Major advances in the identifithat HOX genes are activated by retinoic acid and percation of growth factors and their specific receptors haps by peptide growth factors such as TGF, activin, have significantly improved our understanding of . Simeone et al. reported that in emmatopoiesis. However, the molecular processes controlbryonal carcinoma (EC) cells induced to differentiate ling proliferation and differentiation operating within by retinoic acid HOX genes are sequentially activated hematopoietic cells are not clearly defined.
in a 3-to-5 order (15,16). Furthermore, HOX genes In recent years, there has been great interest in a may be autoregulated by their own products or confamily of regulatory genes implicated in the control of trolled by other HOX proteins, although the mechanism developmental processes, the homeobox genes. Genes of these complex interactions remains largely undeof this family contain a conserved sequence of 183 nufined (18 -20). Moreover, the mammalian homologues cleotides, the homeobox, which encodes a 61-aminoof some Drosophila genes, which appear to positively acid helix-turn-helix type of DNA-binding motif, the or negatively regulate homeobox genes, have been idenhomeodomain (HD) (2 -4). The homeobox was origitified. The MLL gene, homologue of trithorax, was originally discovered in genes controlling Drosophila develnally discovered at the translocation breakpoints in huopment (5) and subsequently has been isolated from man acute leukemias and appears to be responsible for essentially all animal species, including nematodes and the maintanance rather than the initiation of HOX vertebrates (6,7).
gene expression in the embryo (21 -23). Mll deficiency Different homeobox gene families have evolved that in the mouse is embryonic lethal and is associated with encode HDs of different types or classes. Among these altered HOX gene expression along the anterior-poste-HDs, the Drosophila Antennapaedia (Antp) defines one rior axis (24). In contrast, genes of the Polycomb Group consensus sequence referred to as class I HDs (8), appear to exert inhibitory regulatory effects on HOX which is the focus of this review. Mammalian class I genes (25). homeobox genes are organized in four clusters (HOX Homeobox genes appear to be strong candidate genes loci) that presumably evolved by quadruplication of an to regulate hematopoiesis. A number of studies have ancestral gene cluster (Fig. 1) (9,10). Furthermore, indicated that homeobox genes are expressed in blood class I HDs may be grouped in subclasses or homology cells. Furthermore, homeobox-containing genes have groups on the basis of the primary sequence. This alignbeen involved in translocation events in certain leukement defines 13 paralogous groups. Strikingly, the ormic cells, suggesting that mutant forms of these genes der of genes within each cluster is also highly conserved may be important in oncogenesis. In addition, other throughout evolution, suggesting that the physical orstudies have indicated that modulation of homeobox ganization of HOX genes may be crucial for their corgene expression may induce alterations in proliferative, rect deployment (11). Moreover, in Drosophila the order of homeotic genes on the chromosome is colinear with the patterns of expression in the body, with the most Contract grant sponsor: Italian Association for Cancer Research; proximal gene having the most anterior limit of expres-Contract grant sponsor: Department of Veterans Affairs; Contract sion. This rule applies also to vertebrates, as there is grant sponsor: NIH; Contract grant number: RO1DK48642; Con- tract grant sponsor: VA Career Development Award. colinearity between the order of HOX genes within a cluster and patterns of expression in the embryo along *Correspondence to: Maria Cristina Magli, Ph.D., Institute of Mu- the spinal axis and along the proximal-distal axis of tagenesis and Differentiation, CNR,