Expression and function of leptin receptor isoforms in myeloid leukemia and myelodysplastic syndromes: Proliferative and anti-apoptotic activities

The receptor for the gene product of the obesity gene, leptin, was recently reported to be expressed on murine and human hematopoietic progenitor cell s. Therefore, we studied the expression of the leptin receptor, OB-R, in no rmal myeloid precursors, human leukemia cell lines, and primary leukemic ce lls using reverse-transcriptase polymerase chain reaction. In normal hemato poiesis, OB-R was expressed in CD34(+) cells. Normal promyelocytes (CD34(-) 33(+) and CD34(-)13(+)) expressed only very low revels of the short, presum ably nonsignaling isoform. Both the long and short isoforms of OB-R were ex pressed in 10 of 22 samples from patients with newly diagnosed primary or s econdary acute myeloid leukemia (AML), with a higher incidence of the long isoform in primary AML (87.6% v 28.6%; P =.01). The incidence of OB-R expre ssion was higher in recurrent than in newly diagnosed AML (P <.001), and sa mples from four patients with refractory AML showed strong expression of bo th isoforms. Both OB-R isoforms were also expressed in newly diagnosed and recurrent acute promyelocytic leukemia cells but were essentially absent in samples of chronic or acute lymphocytic leukemia. In vitro growth of myelo id leukemic cell lines and of blasts from 14 primary AMLs demonstrated that recombinant human leptin alone induced low level proliferation, significan tly (P < .05) increased proliferation induced by recombinant human granuloc yte colony-stimulating factor, interleukin 3, and stem cell factor in a sub set of AML and increased colony formation (P < .005). Also, leptin reduced apoptosis induced by cytokine withdrawal in MO7E and TF-1 cells. serum lept in levels correlated only with body mass index (P < .001) and gender (P = . 03). Results confirm the reported expression of leptin receptor in normal C D34(+) cells and demonstrate the frequent expression of leptin receptors in AML blasts. While normal promyelocytes lack receptor expression, leukemic promyelocytes express both isoforms. We also demonstrate proliferative effe cts of leptin alone and in combination with other physiologic cytokines, an d antiapoptotic properties of leptin. These findings could have implication s for the pathophysiology of AML. (C) 1999 by The American Society of Hemat ology.