Signaling through CD44 affects cell cycle progression and c-Jun expression in acute myeloid leukemia cells

We present here the first evidence linking CD44 signaling to c-Jun
expression and cell cycle progression in myeloid cell line models.
CD44 ligation with the anti-CD44 monoclonal antibodies have been
shown to induce differentiation and inhibit the proliferation of
human acute myeloid leukemia (AML) cells, and c-Jun is involved in
the regulation of these processes. The effects of anti-CD44
monoclonal antibody A3D8, on myeloid cells were associated with
specific disruption of cell cycle events and induction of G0/G1
arrest. Induction of G0/G1 arrest was accompanied by an increase in
the expression of p21, attenuation of pRb phosphorylation and
associated with decreased CDK2 and CDK4 kinase activities. We
observed that A3D8 treatment of AML patient blasts and HL60/U937
cells led to the downregulation of c-Jun expression at mRNA and
protein level. Transient transfection studies showed the inhibition
of c-jun promoter activity by A3D8, involving both AP-1 sites.
Furthermore, A3D8 treatment caused a decrease in JNK protein
expression and a decrease in the level of phosphorylated c-Jun.
Ectopic overexpression of c-Jun in HL60 cells was able to induce
proliferation and prevent the anti-proliferative effects of A3D8.
Targeting of G1 regulatory proteins and the resulting induction of
G1 arrest by A3D8 may provide new insights into anti-proliferative
and differentiation therapy of AML.