HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors

Abstract

An important target in the understanding of the pathogenesis of acute myeloid leukemias (AML) relies on deciphering the molecular features of normal and leukemic hemopoietic progenitors. In particular, the analysis of the mechanisms involved in the regulation of cell proliferation is decisive for the establishment of new targeted therapies. To gain further insight into this topic we report herein a novel approach by analyzing the role of HERG K + channels in the regulation of hemopoietic cell proliferation. These channels, encoded by the human ether-agò -gò -related gene (herg), belong to a family of K + channels, whose role in oncogenesis has been recently demonstrated. We report here that herg is switched off in normal peripheral blood mononuclear cells (PBMNC) as well as in circulating CD34 + cells, however, it is rapidly turned on in the latter upon induction of the mitotic cycle. Moreover, herg appears to be constitutively activated in leukemic cell lines as well as in the majority of circulating blasts from primary AML. Evidence is also provided that HERG channel activity regulates cell proliferation in stimulated CD34 + as well as in blast cells from AML patients. These results open new perspectives on the pathogenetic role of HERG K + channels in leukemias.

Identification and Functional Characterization of Ion Channels in CD34+ Hematopoietic Stem Cells from Human Peripheral Blood

“…For these reasons, the identification and characterization of ion channels expressed by CD34 + HSCs are essential prerequisites for biotechnological manipulation or physiological understanding of this cell type. However, direct investigations of ion channel function in CD34 + HSCs are rare and primarily focus on cancer cell lines (Korper et al, 2003;Pillozzi et al, 2002;Shirihai et al, 1998). One study using primary CD34 + HSCs demonstrated the inwardly rectifying K + currents but did not systemically examine the other ion channels (Shirihai et al, 1998).…”

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

“…Concordantly, some K ϩ channels are upregulated during tumorigenesis and are pro-oncogenic. For example, the HERG channel is constitutively activated in a broad range of cancer cell types, and HERG-mediated K ϩ currents stimulate proliferation of several cell types (48,49). Similarly, the TASK3 channel is up-regulated in a variety of cancers and has been demonstrated to stimulate tumor cell proliferation and apoptosis resistance; mutation of the K ϩ filter abrogated both channel function and proliferative effects (50).…”

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

“…The human ether a gò-gò related (hERG1) channels (KCNH2 or Kv 11.1, according to the most recent nomenclature) are voltagedependent K þ channels that are overexpressed in human endometrial adenocarcinoma (Cherubini et al, 2000), myeloid leukaemia (Pillozzi et al, 2002) and colorectal cancer (Lastraioli et al, 2004). In addition, they are often overexpressed in neoplastic cell lines of different origin.…”