Role of STAT3 in Transformation and Drug Resistance in CML

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.

Keywords: STAT3; bone marrow microenvironment; chronic myeloid leukemia; drug resistance; transformation.

Figure 1

Activation and regulation of the STAT3 signaling pathway. The STAT3 signaling pathway is turned on by the activation of cell surface receptor (growth factor or cytokine receptors) leading to recruitment and activation of JAK-family of proteins, which in turn recruits and phosphorylates STAT3. STAT3 can also be directly phosphorylated by non-tyrosine kinase receptors (Src or c-abl). Phosphorylated STAT3 homodimerizes and translocates to the nucleus where it regulates gene expression. The signaling pathway can be switched off by the actions of a phosphatase which dephosphorylates STAT3 and prevents dimer formation. Also, PIAS and SOCS family of protein can directly compete with STAT3 for either binding opportunities with the activating receptor or for dimerization and translocation into the nucleus. STAT3, signal transducers and activators of transcription 3; JAK, Janus kinase; SOCS, suppressors of cytokine signaling; PTP, protein-tyrosine phosphatase; PIAS, protein inhibitor of activated STATs.

Figure 2

Regulation of self-renewal and differentiation in bcr–abl transformed murine embryonic stem cell. In bcr–abl transformed murine embryonic stem cell, STAT3 is activated in the LIF-independent MEKK1-dependent manner. Activation of MEKK1 by bcr–abl also leads to activation of Erk 1/2. It has been proposed that increased STAT3 activity within the stem cell promotes self-renewal and inhibition of differentiation, however decreased STAT3 activity leads to increased Erk 1/2 activity which in turn promotes rapid differentiation. This model has to be tested in bcr–abl transformed human stem cells. STAT3, signal transducers and activators of transcription 3; LIFR, leukemia inhibitory factor; Erk 1/2, extracellular signal-regulated kinases 1/2; MEKK1, mitogen-activated protein kinase kinase kinase.

Figure 3

Mechanism for persistence of CML cells in the BM microenvironment. After the acquisition of the oncogene BCR–ABL, cells are dependent on bcr–abl for proliferation, survival, and differentiation (oncogenic addiction). In circulating CML cells, shut down of the kinase activity by use of a bcr–abl kinase inhibitor results in cell death and decrease in circulating CML cell burden. However, within the BM microenvironment, CML cells do not dependent upon bcr–abl activity for survival. These cells depend on the adhesion and soluble factor-mediated signaling for survival within the BM. In this scenario, inhibition of the bcr–abl kinase activity has no effect on the survival of the CML cells leading to the persistence of disease within the BM (minimal residual disease).