Homeobox (hox) genes encode transcription factors which are critically involved in embryonic development. The 39 different hox genes are organized into four unlinked chromosomal gene clusters (hoxA-D) in mammals and a number of studies have suggested that hox genes play important roles in human leukemogenesis. Acute promyelocytic leukemia (APL) cells carrying the PML-RARa fusion protein, respond well by differentiating in their response to an all-trans-retinoic acid (ATRA) treatment. We examined the expression of the individual hox genes during this differentiation. Besides the constitutive expression of hoxA9 and no expression of hoxB7, the expression of hoxC4 increased significantly during differentiation of NB4 cells (PML-RAR(alpha)+). We also examined the expression of hoxC4 in bone marrow cells from APL patients and found that the hoxC4 expression was reproducibly induced during an ATRA treatment. To further examine this finding, HoxC4 was stably expressed in NB4 cells by retroviral transduction. The NB4 cells expressing HoxC4 showed differentiated phenotypes including a CD14 expression, which strongly suggests that upregulated hoxC4 is functionally involved in NB4 cell differentiation in response to ATRA. Upregulation of CD14 is at the transcription level and mediated by the homeodomain of the HoxC4.