Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 117 (3), 902-14

Chemotherapy Resistance in Acute Lymphoblastic Leukemia Requires hERG1 Channels and Is Overcome by hERG1 Blockers

Affiliations

Chemotherapy Resistance in Acute Lymphoblastic Leukemia Requires hERG1 Channels and Is Overcome by hERG1 Blockers

Serena Pillozzi et al. Blood.

Abstract

Bone marrow mesenchymal cells (MSCs) can protect leukemic cells from chemotherapy, thus increasing their survival rate. We studied the potential molecular mechanisms underlying this effect in acute lymphoblastic leukemia (ALL) cells. Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1 (human ether-à-go-go-related gene 1) channels, the β(1)-integrin subunit, and the chemokine receptor CXC chemokine receptor-4. The assembly of such a protein complex activated both the extracellular signal-related kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/Akt prosurvival signaling pathways. At the same time, ALL cells became markedly resistant to chemotherapy-induced apoptosis. hERG1 channel function appeared to be important for both the initiation of prosurvival signals and the development of drug resistance, because specific channel blockers decreased the protective effect of MSCs. NOD/SCID mice engrafted with ALL cells and treated with channel blockers showed reduced leukemic infiltration and had higher survival rates. Moreover, hERG1 blockade enhanced the therapeutic effect produced by corticosteroids. Our findings provide a rationale for clinical testing of hERG1 blockers in the context of antileukemic therapy for patients with ALL.

Similar articles

See all similar articles

Cited by 45 PubMed Central articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback