Signaling pathways

In retrospect, lack of receptor and ligand mutations may not be surprising. It is now recognized that PV progenitor cells are abnormally responsive to multiple growth factors. This suggests that the defect may be in a common signaling pathway (Figure 9.8). Several pathways are involved in processing the response to a cytokine. Each pathway incorporates a complex array of both activating and inhibitory components to ensure an appropriate response is achieved. For example, the EPO/EPOR pathway involves activation of the JAK2/STAT5 and other signal transduction pathways. Negative regulators, such as SHP-1 and the SOCS proteins, ensure that the cellular response to EPO is controlled and appropriate.

Only a small number of signal transduction components have been assessed for mutations in MPD. The SHP-1 phos-phatase was considered a good candidate since it interacts with a number of cytokine receptors, including EPOR, and negatively regulates EPO-induced signal transduction. Hence, such a phosphatase could be a candidate tumor suppressor protein. No mutations were detected in PV or ET patients, and transcript, protein and promoter methylation status were normal. Signaling via TGF-P 1 is achieved through a series of SMAD proteins. Mutations of SMAD2 and SMAD4 are common in solid tumors, such as colorectal cancer. However, mutations of the SMAD genes have not been detected in hematological malignancies.

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