PML-RARalpha 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-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.
Tabe
Yoko
Y
Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Konopleva
Marina
M
Munsell
Mark F
MF
Marini
Frank C
FC
Zompetta
Claudia
C
McQueen
Teresa
T
Tsao
Twee
T
Zhao
Shourong
S
Pierce
Sherry
S
Igari
Jun
J
Estey
Elihu H
EH
Andreeff
Michael
M
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002450:Cell Communication; D002454:Cell Differentiation; D002455:Cell Division; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020738:Leptin / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis*; D010766:Phosphorylation; D020033:Protein Isoforms; D011956:Receptors, Cell Surface / Q000378:metabolism*; D054411:Receptors, Leptin; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D020738:Leptin; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D018168:Receptors, Retinoic Acid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin