PML-RAR is associated with leptin-receptor induction: the role of mesenchymal stem cell–derived adipocytes in APL cell survival

Leptin is secreted by bone marrow (BM) adipocytes and stromal cells and was shown to stimulate myeloid proliferation. We here report that primary acute promyelocytic leukemia (APL) cells express high levels of the leptin-receptor (OB-R) long isoform. In cells with regulated promyelocytic leukemia–retinoic acid receptor (PML-RAR ) expression, inducing PMLRAR was found to increase OB-R levels. We then investigated the effects of leptin produced by BM adipocytes on APL cells using a coculture system with mesenchymal stem cell (MSC)–derived adipocytes. In PML-RAR –expressing cells, all-trans retinoic acid (ATRA)– and doxorubicininduced apoptosis were significantly reduced by coculture with adipocytedifferentiated MSCs. This antiapoptotic effect required direct cell-to-cell interactions, was associated with phosphorylation of signal transducer and activator of transcription-3 (STAT3) and mitogenactivated protein kinase (MAPK), and was reduced by blocking OB-R. This report provides a mechanistic basis for the BM adipocyte–leukemia cell interaction and suggests that OB-R receptor blockade may have therapeutic use in APL. (Blood. 2004;103:1815-1822)