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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2001-11-0134.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4123-4128
NEOPLASIA
Prevention of leptin binding to its receptor suppresses rat
leukemic cell growth by inhibiting angiogenesis
Per Ole Iversen,
Christian Andre Drevon, and
Janne Elin Reseland
From the Institute for Nutrition Research, University
of Oslo, Norway.
Leptin promotes the growth and viability of hematopoietic cells,
and it also stimulates microvessel formation, indicating a role for
leptin in angiogenesis. Acute myelocytic leukemia (AML) remains a
disease with poor prognosis. Similar to solid tumors, it probably
requires angiogenesis to ensure adequate supplies of nutrients. We
studied rats with transplanted AML to test if a neutralizing
anti-leptin receptor monoclonal antibody (mAb) (anti-OB-R) could
inhibit leukemogenesis. At 4 weeks after transplantation, the bone
marrow contained about 80% leukemic cells as assayed with a specific
mAb and flow cytometry. Microscopic examination of bone marrow sections
stained with an anti-von Willebrand mAb revealed a marked increase in
microvessel density in the leukemic rats compared with controls.
Treatment with anti-OB-R for 3 weeks more than halved the content of
bone marrow leukemic cells with a concomitant, substantial decrease in
angiogenesis. A parallel experiment using an irrelevant anticasein mAb
showed no effect on either leukemic cell growth or angiogenesis. We
could not detect surface expression of the leptin receptor on the
leukemic cells, but on mononuclear cells from healthy rats. The
anti-OB-R did not affect in vitro proliferation of leukemic cells
whereas proliferation of the mononuclear cells was markedly impaired.
The anti-OB-R had no effect on either leukemic cell growth or
angiogenesis in leukemic fa/fa rats with a mutated leptin
receptor. We conclude that leptin stimulates leukemic cell growth in
vivo by promoting angiogenesis. Inhibition of binding of leptin to its
receptor might be a new adjunct therapy in AML.
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