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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1668-1676
Expression and Function of Leptin Receptor Isoforms in Myeloid
Leukemia and Myelodysplastic Syndromes: Proliferative and
Anti-Apoptotic Activities
Marina Konopleva,
Adel Mikhail,
Zeev Estrov,
Shourong Zhao,
David Harris,
Gisela Sanchez-Williams,
Steven M. Kornblau,
Joan Dong,
Kay-Oliver Kliche,
Shuwei Jiang,
H. Ralph Snodgrass,
Elihu H. Estey, and
Michael Andreeff
From The University of Texas M.D. Anderson Cancer Center, Houston,
TX; and Progenitor, Inc, Menlo Park, CA.
The receptor for the gene product of the obesity gene, leptin, was
recently reported to be expressed on murine and human hematopoietic progenitor cells. Therefore, we studied the expression of the leptin
receptor, OB-R, in normal myeloid precursors, human leukemia cell
lines, and primary leukemic cells using reverse-transcriptase polymerase chain reaction. In normal hematopoiesis, OB-R was expressed in CD34+ cells. Normal promyelocytes
(CD34 33+ and
CD3413+) expressed only very low levels
of the short, presumably nonsignaling isoform. Both the long and short
isoforms of OB-R were expressed in 10 of 22 samples from patients with
newly diagnosed primary or secondary 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 expression was
higher in recurrent than in newly diagnosed AML (P < .001),
and samples from four patients with refractory AML showed strong
expression of both 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 myeloid leukemic cell lines and of blasts
from 14 primary AMLs demonstrated that recombinant human leptin alone
induced low level proliferation, significantly (P < .05)
increased proliferation induced by recombinant human granulocyte
colony-stimulating factor, interleukin 3, and stem cell factor in a
subset of AML and increased colony formation (P < .005).
Also, leptin reduced apoptosis induced by cytokine withdrawal in MO7E
and TF-1 cells. Serum leptin levels correlated only with body mass
index (P < .001) and gender (P = .03). Results
confirm the reported expression of leptin receptor in normal
CD34+ 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 effects of leptin alone and in
combination with other physiologic cytokines, and anti-apoptotic
properties of leptin. These findings could have implications for the
pathophysiology of AML.
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