The evidence for the promising potential for derivatives of
Vitamin D (deltanoids) in the treatment of
myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid
tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of
myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of
Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the
MEK-ERK and
JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector
C/EBPbeta. As in other cells, the abundance of VDR
protein increases shortly after an exposure of HL60 cells to
1alpha,25-dihydroxyvitamin D(3) (1alpha,25(
OH)(2) D(3)). Other early events include a parallel upregulation of
kinase suppressor of Ras (KSR-1) and the activation of the ERK MAPK pathway and data suggest that KSR-1 acts to amplify the signal provided by low concentrations of 1alpha,25(
OH)(2) D(3). Maintenance of monocytic differentiation may be enhanced by JNK, but diminished by
p38, MAPK signaling. Downstream, one of the targets of these pathways is
C/EBPbeta, which can directly interact with the promoter for CD14, a gene characteristically expressed in monocytes. Importantly, in freshly obtained
acute myeloid leukemia (AML)-M2 cells exposed to
PRI-2191, a novel deltanoid with a modified side chain, upregulation of
C/EBPbeta paralleled the induction of monocytic differentiation. These data provide a basis for the hypothesis that deltanoid-induced upregulation of
C/EBPbeta bypasses the block to granulocytic differentiation in
myeloid leukemia cells by redirecting the cells to monocytic differentiation.