Abstract
Ca(2+) signaling is an important component of signal transduction pathways regulating B and T lymphocyte proliferation, but the functional role of Ca(2+) signaling in regulating myeloid leukemia cell proliferation has been largely unexplored. We observe that the activated (autophosphorylated) Ca(2+)/calmodulin-dependent protein kinase IIgamma (CaMKIIgamma) 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 CaMKIIgamma autophosphorylation. In cells harboring the bcr-abl oncogene, the activation (autophosphorylation) of CaMKIIgamma is regulated by this oncogene. Moreover, inhibition of CaMKIIgamma 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 (GSK3beta)/beta-catenin pathways. In myeloid leukemia cells, CaMKIIgamma directly phosphorylates Stat3 and enhances its transcriptional activity. Thus, CaMKIIgamma is a critical regulator of multiple signaling networks regulating the proliferation of myeloid leukemia cells. Inhibiting CaMKIIgamma may represent a novel approach in the targeted therapy of myeloid leukemia.
Highlights
The myeloid leukemias, including acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), are neoplastic disorders characterized by the aberrant proliferation and differentiation of myeloid precursor cells
We previously observed that CaMKIIg is the calmodulin-dependent protein kinase II; (CaMKII) isoform that is predominantly expressed in myeloid cells [25]
We observe that relatively high amounts of the autophosphorylated CaMKIIg are invariably present in myeloid leukemia cell lines, and this activation is observed in the majority of primary patient AML samples
Summary
The myeloid leukemias, including acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), are neoplastic disorders characterized by the aberrant proliferation and differentiation of myeloid precursor cells. AML is a remarkably heterogenous disease and is associated with multiple different types of genetic mutations These mutations are generally of two functional types, including those which [1] interfere with the differentiation of myeloid precursors and [2] dysregulate the proliferation and viability of these myeloid precursors [1]. Doi:10.1158/0008-5472.CAN-07-2509 genes interfere with the differentiation of myeloid precursors, whereas mutations involving tyrosine kinase receptors such as c-kit [5] and flt-3 [6] dysregulate their proliferation and viability. In CML, the oncogenic bcr-abl tyrosine kinase that is generated by the Philadelphia chromosome is associated with the activation of multiple downstream signal transduction pathways, including Stat5 [11], MAPK [12], PI3K [13], and SRC family kinases [14]
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