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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1815-1822.
Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-03-0802.
Submitted March 19, 2003
Accepted October 7, 2003
PML-RAR is associated with leptin-receptor induction: the role of mesenchymal stem cell-derived adipocytes in APL cell survival
Yoko Tabe, Marina Konopleva, Mark F Munsell, Frank C Marini, Claudia Zompetta, Teresa McQueen, Twee Tsao, Shourong Zhao, Sherry Pierce, Jun Igari, Elihu H Estey, and Michael Andreeff*
Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Clinical Pathology, Juntendo University of Medicine, Tokyo, Japan
* Corresponding author; email: mandreef{at}mdanderson.org.
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 PML-RAR expression, induction of PML-RAR was found to increase levels of OB-R. 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, ATRA- and doxorubicin-induced apoptosis was significantly reduced by coculture with adipocyte-differentiated MSC. This antiapoptotic effect required direct cell-to-cell interactions, was associated with phosphorylation of STAT3 and MAPK and was reduced by blocking OB-R. This report provides a mechanistic basis for the bone marrow adipocyte-leukemia cell interaction and suggests that OB-R receptor blockade may have therapeutic utility in APL.
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