The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation

Abstract

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 eighttwenty-one corepressor-9a), of t(8;21). To understand the leukemic potential of AML1-ETO9a, we performed microarray analysis with the murine multipotential hematopoietic FDCPmix 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.

t(8;21)(q22;q22) fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression

“…Examples might include their role in regulating MDR1 promoter activity and Notch target gene expression. 55,56 It is worth noting that among our cloned multimerized AML1-binding sites for AML1, AML1-ETO, and its C-terminal truncated form (Table S1) and upstream regions of potential AML1-ETO target genes 46 (and data not shown), a putative new variation of the consensus-binding site TG C / T GGTtN (0-13) TGCGGT is present in 50% to 86% of the double site sequences. The orientation of these duplicated sites was predominantly the same.…”

“…46 SPARC is a secreted calcium-binding matricellular glycoprotein and has roles in the regulation of cell adhesion, proliferation, tumorigenesis, metastasis, and efficient platelet production. [47][48][49] The human SPARC gene contains an ACCACA13nTGCGGT sequence in its upstream regulatory promoter region.…”

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

“…One possible explanation for these findings is that the activation of PAX5 and CD19 expression requires transformation and a second genetic alteration. However, even an AML created by the induction of RUNX1/RUNX1T1 in combination with other mutations in the mouse still failed to express CD19 (Schessl et al, 2005;Nishida et al, 2006;Peterson et al, 2007b). It is therefore likely that the formation of CD19 expressing t(8;21) cells in the bone marrow of patients requires additional epigenetic alterations occurring during the selection of highly proliferating transformed leukemic clones.…”

CD44 in hematological neoplasias

“…The t (8;21) translocation in AML is associated with upregulated CD44 both on mRNA and protein level [104]. This characteristic possibly allows detection of tumor cells at a sub-microscopical level [105].…”