All-trans retinoic acid and 1 alpha,25-dihydroxyvitamin D3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes.
A basis for differentiation therapy of leukemias is provided by knowledge of agents which induce specific lineage maturation. All-trans retinoic acid (RA) induces differentiation of HL60 cells to neutrophils and is used to treat acute promyelocytic leukemia. We observed that RA did not induced neutrophil differentiation in serum-free grown HL60 cells whereas 50 nM 1 alpha,25-dihydroxyvitamin D3 (D3) induced maximal monocyte differentiation. Increasing RA concentrations reduced the D3 concentration required for monocyte differentiation. Cells treated with 5 nM D3 showed little response, but differentiated maximally with 5 nM D3 and 10 nM RA. The D3 analogs MC903, EB1089 and KH1060 were more potent inducers of monocyte differentiation. The extent to which analog activity was increased after cotreatment with RA was inversely related to potency. Twenty-four hour treatment with 10 nM RA primed cells for response to 5 nM D3; the reverse sequence being ineffective. Priming with 10 nM RA, or subsequent treatment with D3 (5 nM), did not alter expression of mRNAs encoding receptors for D3 (VDR), RA (RAR alpha) or 9-CIS RA (RXR alpha, beta, gamma). That RA promotes both neutrophil and monocyte differentiation has implications for the use of RA and D3 in treatment of leukemias and provides insight into mechanisms whereby RAR, VDR and RXR facilitate monocyte differentiation.
Brown
G
G
Department of Immunology, University of Birmingham, Edgbaston, UK.
Bunce
C M
CM
Rowlands
D C
DC
Williams
G R
GR
D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D002117:Calcitriol