hERG1 K+ channels are expressed in a broad range of human leukemic cell lines and primary acute myeloid and lymphoid leukemias (

Pillozzi S, et al
Leukemia
16
:
1791
–1798,
2002
;
Smith GA, et al,
JBC
227
:
18528
–18534,
2002
). hERG1 activity is necessary for leukemia cell proliferation as well as migration in response to angiogenic factors (VEGF). This effect can be traced back to the assembly of a macromolecular signaling complex on the plasma membrane of leukemia cells. Such complex comprises hERG1 channels, the beta1 subunit of integrin adhesion receptors and the VEGF receptor 1, FLT-1. In vivo experiments in NOD/SCID mice injected with AML cells showed that herg1 over-expression confers a greater malignancy, witnessed by a higher bone marrow (BM) angiogenesis, and a stronger leukemia blast exit into the peripheral blood (PB) and into extramedullary organs. What is more, herg1 expression in AML patients correlates with a higher probability of relapse and shorter survival periods (
Pillozzi S et al,
Blood
110
:
1238
–1250,
2007
). On the whole we can conclude that hERG1 channel expression in AML represent a progression factor and can be envisaged as a novel target for therapy. We tested this latter hypothesis in NOD/SCID mice injected with AML cell lines expressing hERG1 channels at various extent, and treating injected mice with a selective hERG1 inhibitor, E4031. E4031 was administered i.p. starting one week after inoculum, at the dose of 20 mg/kg, daily for two weeks. In a first set of experiments mice were sacrificed after a total 3 weeks after inoculum. It emerged that E4031 reduced both BM engraftment and PB invasion of AML cells. In particular, BM angiogenesis was significantly lower in mice treated with E4031. In a second set of experiments, mice were treated as above and the survival time was measured. It emerged that E4031 treatment prolonged survival compared with the control-treated group. We have developed a monoclonal antibody against an extracellular loop of hERG1 channels. The immunoreactivity and activity on hERG1 channels of such antibody was first tested in leukaemia cells. Treatment of NOD/SCID mice injected with AML cell lines with this antibody is ongoing.

Topics:
adhesions, angiogenesis factor, antibodies, cancer, cd29 antigen, cell lines, diabetes mellitus, engraftment, integrins, leukemia

Author notes

Disclosure: No relevant conflicts of interest to declare.

2007, The American Society of Hematology
2007
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