Glutamate-mediated NMDA Receptor Induces Ca2+ Entry And Increases Growth Of Leukaemic Megakaryoblasts | 29523
Journal of Cancer Science & Therapy
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The discovery of CALR mutations in myeloproliferative neoplasms highlighted importance of Ca2+ homeostasis in
megakaryocytic cells. Megakaryocytes express N-methyl-D-aspartate receptors (NMDARs) known to mediate glutamateinduced
Ca2+ entry in other cells. However, the roles of glutamate and NMDARs in normal and malignant megakaryocytes are
not known. The aim of this study was to determine whether NMDARs provide a novel pathway for Ca2+ entry into leukaemic
megakaryoblasts and if so, whether modulating NMDAR activity could influence leukaemia cell growth. Expression of NMDAR
subunits was examined in human bone marrow including neoplastic and megakaryoblastic leukaemia cell lines (Meg-01,
Set-2 and K-562). Well-established NMDAR modulators (agonists and antagonists) were employed to determine NMDAR
effects on the levels of intracellular Ca2+, cell viability, proliferation and differentiation. We found that human leukaemic cells
expressed distinct combinations of the NMDAR subunits. Low concentrations of glutamate and NMDAR antagonists (riluzole,
memantine, MK-801 and AP5; 5-100 ?M) attenuated cell growth in culture mostly through the inhibition of cell proliferation.
The use-dependent NMDAR antagonist, memantine (100 ?M) reduced Meg-01 viability to 16±10% of controls (IC50 20 ?M)
and inhibited Meg-01 proliferation to 41±6% (IC50 36 ?M). Further, after three days in the presence of NMDAR antagonists,
cells acquired morphologic and immunophenotypic features of megakaryocytic differentiation. Our findings indicate that
NMDARs provide a novel pathway for Ca2+ entry into leukaemic megakaryoblasts that supports cell proliferation. NMDAR
inhibitors counteract these effects suggesting a novel way to interrupt growth of this type of leukaemia.
Tania Kamal is a PhD student at The University of Auckland, New Zealand.
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