leptin and Leukemia--Promyelocytic--Acute

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-RARalpha) expression, inducing PML-RARalpha 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-RARalpha-expressing cells, all-trans retinoic acid (ATRA)- and doxorubicin-induced apoptosis were significantly reduced by coculture with adipocyte-differentiated MSCs. This antiapoptotic effect required direct cell-to-cell interactions, was associated with phosphorylation of signal transducer and activator of transcription-3 (STAT3) and mitogen-activated 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.

Topics: Adipocytes; Apoptosis; Blotting, Western; Cell Communication; Cell Differentiation; Cell Division; Coculture Techniques; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunohistochemistry; Leptin; Leukemia, Promyelocytic, Acute; Mesenchymal Stem Cells; Neoplasm Proteins; Oncogene Proteins, Fusion; Phosphorylation; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; Receptors, Retinoic Acid; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Tretinoin; U937 Cells; Up-Regulation

Leptin, secreted by adipocytes in bone marrow stimulates proliferation of acute myeloid leukemia cells. PML-RARalpha-expressing acute promyelocytic leukemia (APL) cells express high levels of leptin receptor (OB-R). Adipocytes derived from mesenchymal stem cells (MSC) protect APL cells from drug-induced apoptosis partially through the interaction of the membrane-bound form of leptin and OB-R. We report that when NB4 APL cells migrated beneath a cultured MSC-derived adipocyte layer, apoptosis in most of the cells below the adipocytes was blocked. Major histocompatibility complex (MHC) expression of NB4 cells and MSCs matched (both were HLA-DR negative and HLA-ABC positive). This match in MHC expression may play a role in the intimate cell-to-cell interactions that support the anti-apoptotic effects of the membrane-bound leptin signaling pathway.

Topics: Adipocytes; Apoptosis; Bone Marrow Cells; Cell Movement; Cells, Cultured; Humans; Leptin; Leukemia, Promyelocytic, Acute; Major Histocompatibility Complex; Mesenchymal Stem Cells; Neoplasm Proteins; Oncogene Proteins, Fusion; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction