HMBA induces MELC to terminal erythroid differentiation. The mechanism of
HMBA action is not known. Culture with
HMBA causes changes in gene expression which occur during the early "latent period", that is, prior to commitment to terminal differentiation. The inducer causes a decrease in
diacylglycerol concentration, a decrease in Ca+2 and a decrease in
phospholipid-dependent
protein kinase C activity (within 2 hr) (Figure 2). There is an early suppression (within 1-2 hrs) of c-myb and c-myc gene transcription and an increase in c-fos
mRNA (within 4 hrs).
HMBA-induced commitment to terminal differentiation is detected by 12 hrs and over 95% become committed cells by 48 to 60 hrs. Commitment is associated with persistent suppression of c-myb gene transcription and elevated levels of c-fos
mRNA whereas the level of c-myc
mRNA returns to that of uninduced cells. By 36 to 48 hrs, transcription of alpha 1 and beta maj
globin genes is increased 10 to 30 fold, while that of rRNA genes is suppressed. It is not yet clear how the
protein products of proto-oncogenes elicit or modify cellular responses. Changes in expression of c-myb, c-myc, c-fos and p53 genes which occur during
HMBA-induced differentiation, as well as in several other systems, suggest that products of these genes may have a role in regulating expression of multiple genes. One possible application of the established pattern of
HMBA-induced modulation of gene expression during MELC differentiation may be in following the effects of cyto-differentiation agents during treatment of
cancers. Phase I and Phase II chemical trials have been initiated to evaluate
HMBA as a cytodifferentiation agent in human
neoplasms (65). For most human
tumors, assay for cytologic evidence of induced differentiation is difficult at best. Following the effects of a differentiation inducing agent by determining c-myc, or c-myb,
mRNA levels may provide useful indicators of
biological activity of
HMBA and be a basis for evaluating whether continued administration of the agent is of interest in terms of potential clinical efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)