In hematological malignancies, structural alterations of genes for G 1-specific cyclin-dependent kinases inhibitors (CKIs) have been extensively investigated. G 1-CKIs might play an important role not only as tumor suppressor genes but also in cellular differentiation. We examined constitutive and differentiation-induced expression and regulation of the four members of the G 1-CKI family p16 INK4A, p15 INK4B, p18 INK4C and p19 INK4D in acute myeloid leukemia as well as their expression in normal granulocytes and monocytes. p18 INK4C and p19 INK4D mRNA were expressed constitutively at high levels in seven myeloid cell lines and 16 AML patient samples, whereas expression of p15 INK4B mRNA was very low and only detectable by nested RT-PCR analysis. During phorbol ester-induced monocytic differentiation of leukemic HL-60 cells expression of particular G 1-CKIs was disparately regulated. This process was associated with growth arrest of the majority of the cells (⩾ 80%) in G 1/G 0, and in parallel p15 INK4B were upregulated whereas p18 INK4C and p19 INK4D expression was downregulated. In contrast, granulocytic differentiation induced by DMSO was accompanied by an increase of p18 INK4C and p19 INK4D expression only. PMA treatment of blast cells from two AML patients confirmed these cell line results. Disparate regulation of p15 INK4B and p18 INK4C mRNA was dependent on intermediary protein synthesis and occurred at the post-transcriptional level as shown by nuclear run-on analysis and mRNA half-life studies. In normal granulocytes and monocytes low constitutive p15 INK4B and p18 INK4C mRNA expression was detectable by RT-PCR only, but p19 INK4D transcripts were noted by Northern blotting in both cell types. Disparate expression of G 1-specific cell cycle inhibitors indicates complex and divergent roles of particular CKIs during normal and leukemic myeloid hematopoiesis.