Abstract
Chronic myeloid leukemia (CML) is initially driven by the bcr–abl fusion oncoprotein. The identification of bcr–abl led to the discovery and rapid translation into the clinic of bcr–abl kinase inhibitors. Although, bcr–abl inhibitors are efficacious, experimental evidence indicates that targeting bcr–abl is not sufficient for elimination of minimal residual disease found within the bone marrow (BM). Experimental evidence indicates that the failure to eliminate the leukemic stem cell contributes to persistent minimal residual disease. Thus curative strategies will likely need to focus on strategies where bcr–abl inhibitors are given in combination with agents that specifically target the leukemic stem cell or the leukemic stem cell niche. One potential target to be exploited is the Janus kinase (JAK)/signal transducers and activators of transcription 3 (STAT3) pathway. Recently using STAT3 conditional knock-out mice it was shown that STAT3 is critical for initiating the disease. Interestingly, in the absence of treatment, STAT3 was not shown to be required for maintenance of the disease, suggesting that STAT3 is required only in the tumor initiating stem cell population (Hoelbl et al., 2010). In the context of the BM microenvironment, STAT3 is activated in a bcr–abl independent manner by the cytokine milieu. Activation of JAK/STAT3 was shown to contribute to cell survival even in the event of complete inhibition of bcr–abl activity within the BM compartment. Taken together, these studies suggest that JAK/STAT3 is an attractive therapeutic target for developing strategies for targeting the JAK–STAT3 pathway in combination with bcr–abl kinase inhibitors and may represent a viable strategy for eliminating or reducing minimal residual disease located in the BM in CML.
Highlights
The signal transducers and activators of transcription 3 (STAT3) was identified as a DNA-binding protein capable of transducing signals from cytokine-stimulated cell surface receptors to the nucleus, where it was capable of selectively binding to a palindromic Interferon (IFN)-γ-activated sequence element and induce transcription of acute-phase genes (Akira et al, 1994; Lutticken et al, 1994; Zhong et al, 1994)
It was already established that; (a) chronic myeloid leukemia (CML) could be diagnosed by the presence of Philadelphia chromosome (Nowell and Hungerford, 1964), (b) the Philadelphia chromosome was created by the reciprocal translocation between chromosomes 9 and 22 and contained a gene called BCR–ABL which encoded for a fusion protein called bcr– abl (Lugo et al, 1990; Gishizky et al, 1993), (c) tyrosine kinase activity of the bcr–abl proteins is required for the transformation into CML (Carlesso et al, 1994), (d) herbimycin A, an inhibitor of tyrosine kinase, showed inhibition of growth in cells expressing bcr–abl (Okabe et al, 1992, 1994a,b)
In most of the cases decrease in the proteins involved in the negative feedback mechanism, results in sustained activation of Janus kinase (JAK)–STAT3 pathway leading to increased progression of CML or to development of resistance toward anti-leukemic drugs
Summary
The signal transducers and activators of transcription 3 (STAT3) was identified as a DNA-binding protein capable of transducing signals from cytokine-stimulated cell surface receptors to the nucleus, where it was capable of selectively binding to a palindromic Interferon (IFN)-γ-activated sequence element and induce transcription of acute-phase genes (Akira et al, 1994; Lutticken et al, 1994; Zhong et al, 1994). By independently utilizing a MEK inhibitor and a MEK1 construct with a dominant negative activity, these same investigators were able to show that phosphorylation of the STAT3 Ser727 residue, but not STAT3 Tyr705 residue, required the activity of MEK in CML cells and in CD34+ CML progenitor cells from two patients (Coppo et al, 2006).
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