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Activation of Stem-Cell Specific Genes by HOXA9 and HOXA10 Homeodomain Proteins in CD34⁺ Human Cord Blood Cells

^a Department of Medicine, Veterans Affairs Medical Center, University of California at San Francisco, California, USA;
^b Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada;
^c Department of Medicine and Comprehensive Cancer Center, University of California at San Francisco, California, USA

Key Words. Hematopoiesis • Hematopoietic stem cells (HSCs) • Homeobox genes • Microarray • Gene expression profiling

Correspondence: H. Jeffrey Lawrence, M.D., Department of Medicine, Hematology Research (151H), Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121, USA. Telephone: 415-221-4810, ext. 3340; Fax: 415-750-6959; e-mail: jeffl{at}medicine.ucsf.edu

There is growing evidence for a role of HOX homeodomain proteins in normal hematopoiesis. Several HOX genes, including HOXA9 and HOXA10, are expressed in primitive hematopoietic cells, implying a role in early hematopoietic differentiation. To identify potential target genes of these two closely related transcription factors, human CD34⁺ umbilical cord blood cells were transduced with vectors expressing either HOXA9 or HOXA10 and analyzed with cDNA micro-arrays. Statistical analysis using significance analysis of microarrays revealed a common signature of several hundred genes, demonstrating that the transcriptomes of HOXA9 and HOXA10 largely overlap in this cellular context. Seven genes that were upregulated by both HOX proteins were validated by real-time reverse transcription polymerase chain reaction. HOXA9 and HOXA10 showed positive regulation of genes in the Wnt pathway, including Wnt10B and two Wnt receptors Frizzled 1 and Frizzled 5, an important pathway for hematopoietic stem cell (HSC) self-renewal. Other validated genes included v-ets-related gene (ERG), Iroquois 3 (IRX3), aldehyde dehydrogenase 1 (ALDH1), and very long–chain acyl-CoA synthetase homolog 1 (VLCS-H1). GenMAPP (Gene Micro Array Pathway Profiler) analysis indicated that HOXA10 repressed expression of several genes involved in heme biosynthesis and three globin genes, indicating a general suppression of erythroid differentiation. A number of genes regulated by HOXA9 and HOXA10 are expressed in normal HSC populations.

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