Abstract
Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs).
Highlights
The mounting evidence that alteration of the same genes (IDH1/2, EZH2, TET2, MLL...) can be found in solid tumours and in haematological malignancies highlights the similarity of oncogenic mechanisms in human malignancy, independently of the tissue origin of the cancer stem cells [1,2,3,4,5,6].For certain genes the knowledge accumulated in solid cancer studies translates poorly to blood malignancies: the MET gene, which encodes the tyrosine-kinase receptor for hepatocyte growth factor (HGF), is one example
We demonstrated that induction in cell lines of JAK2V617F, or its knocking-down, did not affect HGF production, which indicated that the production of HGF by polycythaemia vera (PV)
In pancreatic cancer cells hypoxia increased the expression of HGF activator (HGFA) mRNA and protein, and this effect was inhibited by a siRNA targeting HIF-1
Summary
The mounting evidence that alteration of the same genes (IDH1/2, EZH2, TET2, MLL...) can be found in solid tumours and in haematological malignancies highlights the similarity of oncogenic mechanisms in human malignancy, independently of the tissue origin of the cancer stem cells [1,2,3,4,5,6]. Malignant CML and MPN progenitors produce HGF in an autocrine fashion, and HGF expression levels were reported to have significant prognosis impact in AML and in CML [15,16,17] Both the HGF and MET genes are located on chromosome 7, a chromosome frequently altered in haematological malignancies. Met activation provides signalling for migration via Ras/Raf/MEK/Erk1/2; for cell proliferation and transformation via Stat; for angiogenesis, proliferation and survival via PI3K/Akt/IKK/NF- B; and anti-apoptotic effect and protein synthesis via PI3K/Akt, Gsk , p53 and mTOR [25,26,27,28,29,30]. Ras/Raf/MEK/Erk1/2; proliferation and transformation via Stat; angiogenesis, proliferation and survival via PI3K/Akt/IKK/NF- B; and proliferation-anti-apoptotic effect-protein synthesis via PI3K/Akt-Gsk3 -p53-mTor. The U3 ubiquitin ligase c-Cbl is recruited to Met after activation and is responsible for Met ubiquitinylation and targeted degradation by the proteasome. The object of this review is to gather and summarise published studies of the MET gene in myeloid malignancies, and to provide evidence that drugs currently used in solid tumours to block the HGF/Met axis should be considered for the therapy of chronic myeloid malignancies
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