The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation.
The 8;21 translocation is a common chromosomal abnormality in acute myeloid leukemia (AML). We recently identified a naturally occurring leukemogenic splice variant, AML1-ETO9a (acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor-9a), of t(8;21). To understand the leukemic potential of AML1-ETO9a, we performed microarray analysis with the murine multipotential hematopoietic FDCP-mix A4 cell line. We identified changes in expression of various genes including CD44. CD44 is a type I transmembrane protein and functions as the major cellular adhesion molecule for hyaluronic acid, a component of the extracellular matrix. CD44 is expressed in most human cell types and is implicated in myeloid leukemia pathogenesis. We show that the presence of AML1-ETO9a significantly increased the expression of CD44 at both RNA and protein levels. Furthermore, the CD44 promoter is bound by AML1-ETO9a and AML1-ETO at the chromatin level. In addition, in the AML1-ETO9a leukemia mouse model CD44 is regulated in a cell context-dependent manner. Thus, our observations suggest that AML1-ETO and its splice variant AML1-ETO9a are able to regulate the expression of the CD44 gene, linking the 8;21 translocation to the regulation of a cell adhesion molecule that is involved in the growth and maintenance of the AML blast/stem cells.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
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D000208:Acute Disease; D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D018960:Hyaluronan Receptors; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein