16- hoxA9

16- hoxA9 - StemR Cells C oncise eview HOX and Non-HOX...

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HOX and Non-HOX Homeobox Genes in Leukemic Hematopoiesis B RONWYN M. O WENS , a,b R OBERT G. H AWLEY a,b,c a Hematopoiesis Department, Holland Laboratory, American Red Cross, Rockville, Maryland, USA; b Program in Molecular and Cellular Oncology, Institute for Biomedical Sciences, The George Washington University, Washington, D.C., USA; c Department of Anatomy and Cell Biology, The George Washington University Medical Center, Washington, D.C., USA Key Words. Homeobox genes · Transcription factors · Hematopoiesis · Leukemia A BSTRACT Dysregulation of homeobox (HB)-containing genes is becoming increasingly recognized as the underlying basis of many hematologic malignancies. Expression of clus- tered HB ( HOX ) genes within the hematopoietic system, and enforced overexpression and knockout studies have provided support for the concept that these homeodomain- containing transcription factors play a significant role in the developmental biology of hematopoietic cells. Diverged HB ( non-HOX ) genes have recently been identified as either cofactors and/or accelerators of leukemic disease mediated by HOX genes or as bona fide oncogenes. In this review, we examine the evidence that supports a central role for HB genes in normal and malignant hematopoiesis, paying particular attention to the non-HOX class and the possible mechanisms through which they contribute to leukemic transformation. Stem Cells 2002;20:364-379 S TEM C ELLS 2002;20:364-379 www.StemCells.com Correspondence: Robert G. Hawley, Ph.D., Cell Therapy Research and Development, Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, Maryland 20855, USA. Telephone: 301-738-0420; Fax: 301-738-0444; e-mail: hawleyr@usa.redcross.org Received May 23, 2002; accepted for publication July 17, 2002. ©AlphaMed Press 1066-5099/2002/$5.00/0 I NTRODUCTION The finding of specific chromosomal rearrangements in acute leukemia first suggested that genes at these loci were responsible for transformation [1, 2]. Transcription factors are frequent targets in these lesions, and rearrangements can result in the generation of fusion proteins, as in E2A-PBX1 associated with pre-B-cell acute lymphoblastic leukemia (ALL) or the juxtaposition of tightly regulated genes next to highly active promoter regions. Immunoglobulin (Ig) and T-cell-receptor (TCR) loci are often involved in the latter scenario, most likely due to the fact that these genes normally undergo rearrangement during B- and T-cell development. Evaluation of breakpoint regions within translocations in leukemia patients and retroviral insertion sites associated with hematologic malignancies in murine models has impli- cated several members of the homeodomain-containing (HD) family of transcription factors in leukemogenesis. HD transcription factors contain a 61-amino-acid helix-turn- helix DNA-binding domain [3]. Sequences flanking the HD also influence specificity by coordinating interaction with cofactor proteins that influence DNA-binding properties. HD encoding (homeobox [HB]) genes are broadly
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16- hoxA9 - StemR Cells C oncise eview HOX and Non-HOX...

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