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Activated Ca²⁺/Calmodulin-Dependent Protein Kinase II Is a Critical Regulator of Myeloid Leukemia Cell Proliferation

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Steven J. Collins, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109. Phone: 206-667-4389; Fax: 206-667-6523; E-mail: scollins{at}fhcrc.org.

Key Words: myeloid leukemia • Ca²⁺/calmodulin-dependent protein kinase II • bcr-abl oncogene • Stat3

Ca²⁺ signaling is an important component of signal transduction pathways regulating B and T lymphocyte proliferation, but the functional role of Ca²⁺ signaling in regulating myeloid leukemia cell proliferation has been largely unexplored. We observe that the activated (autophosphorylated) Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is invariably present in myeloid leukemia cell lines as well as in the majority of primary acute myelogenous leukemia patient samples. In contrast, myeloid leukemia cells induced to terminally differentiate or undergo growth arrest display a marked reduction in this CaMKII autophosphorylation. In cells harboring the bcr-abl oncogene, the activation (autophosphorylation) of CaMKII is regulated by this oncogene. Moreover, inhibition of CaMKII activity with pharmacologic agents, dominant-negative constructs, or short hairpin RNAs inhibits the proliferation of myeloid leukemia cells, and this is associated with the inactivation/down-regulation of multiple critical signal transduction networks involving the mitogen-activated protein kinase, Janus-activated kinase/signal transducers and activators of transcription (Jak/Stat), and glycogen synthase kinase (GSK3β)/β-catenin pathways. In myeloid leukemia cells, CaMKII directly phosphorylates Stat3 and enhances its transcriptional activity. Thus, CaMKII is a critical regulator of multiple signaling networks regulating the proliferation of myeloid leukemia cells. Inhibiting CaMKII may represent a novel approach in the targeted therapy of myeloid leukemia. [Cancer Res 2008;68(10):3733–42]