Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells.
Kv1.3 channels regulate proliferation of normal lymphocytes, but the role of voltage-gated potassium channels in transformed hematopoietic cells is not known. We examined transcripts for Kv1.3, h-erg, h-eag, and BEC1 genes in primary lymphocytes and leukemias and in several hematopoietic cell lines. Surprisingly, BEC1, formerly thought to be brain-specific, was present in all the primary leukemias examined, in resting peripheral blood lymphocytes, and in proliferating activated tonsillar cells, lymphocytes from Sjögren's patients, and Epstein-Barr virus-transformed B-cells. Only h-erg mRNA was up-regulated in the cancer cells, but this was not due to proliferation per se, because it was not elevated in any of the proliferating noncancerous lymphocyte types examined. Nor did h-erg transcript levels correlate with the B-cell subset, because it was elevated in immature neoplastic B-CLL cells (CD5(+)) and in a CD5(-) Burkitt's lymphoma cell line (Raji) but not in Sjögren's syndrome cells (enriched in CD5(+) B-cells) or Epstein-Barr virus-transformed B-cells, which are mature CD5(-) B-cells. The protein and whole cell current levels roughly corresponded with the amount of mRNA expressed in three hematopoietic cell lines: CEM (an acute lymphoblastic leukemic line), K562 (a chronic myelogenous leukemic line), and U937 (an acute promyelocytic leukemic line). The selective HERG channel blocker, E-4031, reduced proliferation of CEM, U937, and K562 cells, and this appears to be the first direct evidence of a functional role for the HERG current in cancer cells. Selective up-regulation of h-erg appears to occur in neoplastic hematopoietic cells, thus providing a marker and potential therapeutic target.
Smith
Garth A M
GA
Division of Cellular and Molecular Biology, Toronto Western Research Institute, Toronto, Ontario M5T 2S8, Canada.
Tsui
Hing-Wo
HW
Newell
Evan W
EW
Jiang
Xinpo
X
Zhu
Xiao-Ping
XP
Tsui
Florence W L
FW
Schlichter
Lyanne C
LC
D001483:Base Sequence; D027682:Cation Transport Proteins; D002455:Cell Division / Q000502:physiology; D017931:DNA Primers; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000235:genetics; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D027682:Cation Transport Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG