Homeobox genes in normal hematopoiesis and leukemia.

URING THE PAST DECADE, there have been D major advances in the identification of the growth factors and their specific receptors that regulate differentiation events during Despite these discoveries, the factors that act at the level of gene transcription to effect changes in blood cell phenotype remain largely unidentified. A recent review of the transcription factors involved with hematopoiesis was published in Blood.5 However, many of these transcription factors are widely expressed and seem to serve fairly general cellular functions such as proliferation. Following the identification of homeobox proteins as one of the major classes of transcription factors that control cellular differentiation during development,6,7 there has been increasing interest in the possible role of these proteins as control factors during hematopoiesis. We will review: (1) the aberrant expression of homeobox genes in leukemias; (2) the lineage-specific expression of homeobox genes in leukemic cell lines and normal hematopoietic cells; (3) the hematopoietic effect of modulating homeobox gene expression; and (4) evidence for the specific binding of homeobox proteins to regulatory regions of hematopoietic genes such as globin. Homeobox genes in development. For many years researchers have been aware of a number of genetic mutations in the fruit fly that result in the transformation of one body segment to another. An example of such a so-called homeotic mutation is the condition in which the fly develops leg structures where the antennae normally belong. The gene involved in this mutation was characterized independently by two different laboratories and was named Antennapedia (Ant~). 87~ The homeobox is a highly conserved 183 nucleotide sequence originally discovered by comparison of the Antp gene with several other homeotic genes and subsequently identified in about 25 Drosophila developmental genes that control body segment identity.7 A number of the Drosophila homeobox genes are arranged in a large complex known as the HOM-C cluster. During embryonic development these genes have very precise but overlapping zones of expression from head to tail, with the anterior limit of expression of each gene related to its position in the cluster. Homeobox genes also seem to be master control genes for the development of the mammalian body plan.10 In particular, homeobox gene expression patterns correlate strongly with specific morphologic structures in the developing hindbrain and spinal cord" and in limb buds1* (see below). Recent studies in transgenic mice have shown that homozygous deletion of certain homeobox genes results in specific morphologic defects in neck and facial structures,13J4 as well as thoracic structure^. ^^ Class Z homeobox genes are organized as clusters in the human genome. Approximately 40 mammalian homeobox genes have been designated class I genes because they contain homeodomains that are highly related to the homeobox sequence of Antp. These homeobox genes are arranged in the human and murine genomes as a series of four clusters (Fig l), referred to as HOX1, HOX2, HOX3, and HOX4, each containing 9 to 11 individual genes and located on human chromosomes 7, 17, 12, and 2, and murine chromosomes 6,11,15, and 2, re~pectively. ~6J7 The nomenclature for these clusters of homeobox genes has been confusing, with individual laboratories giving different names to the same genes, and with variable usage of letter and decimal designations to individual HOX genes. Current nomenclature for homeobox genes dictates that the human clusters be labeled HOX1, HOX2, etc, whereas the murine equivalents are Hox-1, Hox-2, etc.18 Individual human HOX genes are given letter designations, eg, HOX2A, HOXlH, etc, whereas the murine homologs are given decimal point designations, eg, Hox-2.1, Hox-1.8, etc. Unfortunately the letter and decimal designations do not pertain to the 5'-to-3' order of the genes in each complex but rather to the order of their discovery. Comparison of the human and murine HOX DNA sequences shows that it is possible to align the four genomic clusters and group these genes into 13 divisions, referred to as paralogs,19 based on a strong vertical conservation within the homeobox domains as well as limited homology outside the homeobox regionsF0 Thus, the paralogs of HOX2A are HOXlC and HOX3D (Fig 1). Furthermore, the genes of the HOX clusters can be aligned with the Drosophila