Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RUNX1-EVI1 is a chimeric gene generated by t(3;21)(q26;q22) observed in patients with aggressive transformation of myelodysplastic syndrome or chronic myelogenous leukemia. RUNX1-EVI1 has oncogenic potentials through dominant-negative effect over wild-type RUNX1, inhibition of Jun kinase (JNK) pathway, stimulation of cell growth via AP-1, suppression of TGF-beta-mediated growth inhibition and repression of C/EBPalpha. Runx1-EVI1 heterozygous knock-in mice die in uteri due to central nervous system (CNS) hemorrhage and severe defects in definitive hematopoiesis as Runx1-/- mice do, indicating that RUNX1-EVI1 dominantly suppresses functions of wild-type RUNX1 in vivo. Acute myelogenous leukemia is induced in mice transplanted with bone marrow cells expressing RUNX1-EVI1, and a Runx1-EVI1 knock-in chimera mouse developed acute megakaryoblastic leukemia. These results suggest that RUNX1-EVI1 plays indispensable roles in leukemogenesis of t(3;21)-positive leukemia. Major leukemogenic effect of RUNX1-EVI1 is mainly through histone deacetyltransferase recruitment via C-terminal binding protein. Histone deacetyltransferase could be a target in molecular therapy of RUNX1-EVI1-expressing leukemia.
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PMID:Role of the RUNX1-EVI1 fusion gene in leukemogenesis. 1901 45

Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.
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PMID:TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. 2013 Jun 50

In the current study, we have examined the efficacy of a Src/Abl kinase inhibitor SKI-606 (Bosutinib) for its effect on prostate cancer growth and skeletal metastasis. Treatment of highly invasive human prostate cancer cells PC-3 and DU-145 with different doses of SKI-606 decreased Src activation, cell proliferation, migration, and invasion as determined by Matrigel Boyden chamber invasion assay. For in vivo studies, PC-3 cells were inoculated through s.c. or i.t. route into male BALB/c nu/nu or Fox Chase severe combined immunodeficient mice, respectively. Experimental animals treated with SKI-606 developed tumors of a significantly smaller volume and a significant decrease (50%) in experimental skeletal lesion area. A marked increase (32%) in bone volume to tumor volume ratio was also seen by micro-computed tomography analysis of tibias from control and experimental groups of animals. Western blot analysis showed the ability of SKI-606 to significantly decrease the phosphorylation of signaling molecules (AKT, mitogen-activated protein kinase, focal adhesion kinase) and the expression of tumor progression-associated genes uPAR, MMP-2, MMP-9, N-cadherin, fibronectin, BMP-2 (bone morphogenetic protein 2), BMP-6 (bone morphogenetic protein 6), IL-8 (interleukin 8), and TGF-beta (transforming growth factor beta) in prostate cancer cells. SKI-606 is currently in clinical trials for breast cancer and chronic myelogenous leukemia. Results from these studies provide convincing evidence for evaluating its efficacy in prostate cancer patients.
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PMID:SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. 2042 91

Transforming growth factor beta 1 (TGF-beta1) is the prototypic member of a large family of structurally related pleiotropic-secreted cytokines. The TGF-beta1/SMAD signaling pathway usually participates in a wide range of cellular processes such as growth, proliferation, differentiation and apoptosis. Upon binding on TGF-beta1, the dimerized TGF-beta type II receptors recruit and phosphorylate the TGF-beta type I receptors, which phosphorylate the receptor-regulated SMAD (SMAD2 and SMAD3) presented by the SMAD anchor for receptor activation. The phosphorylated receptor-regulated SMAD form heterologous complexes with the common-mediator SMAD (SMAD4) and subsequently translocate into the nucleus, where they interact with other transcription factors to regulate the expression of target genes. This multi-functional signaling pathway modulated by various elements with complex mechanisms at different levels is also inevitably involved in cancer. We herein present data on the role of the TGF-beta1/SMAD signaling pathway in human chronic myeloid leukemia and explain the potent biological effects of TGF-beta1 on leukemia cells. The paper is based on a review of articles selected from Cancerline and Medline data bases. The constitutively active tyrosine kinase produced by the specific Bcr-Abl fusion gene on the Philadelphia chromosome can enhance the resistance of malignant cells to TGF-beta1-induced growth inhibition and apoptosis, which contributes to enhancement of proteasomal degradation of p27. However, overexpression of the EVI1 gene, which is also caused by Bcr-Abl, can recruit the C-terminal binding protein and histone deacetylase to prevent the MH2 domain on SMAD3. The later is essential for transcription activation on target genes and leads to blockage of the TGF-beta1/SMAD signaling pathway. Some studies have indicated that certain therapeutic agents applied in clinical treatment can inhibit proliferation and promote differentiation of leukemia cells by way of modulation of the TGF-beta1/SMAD signal pathway. For example, arsenic trioxide can promote specific degradation of the AML1/MDS1/EVI1 oncoprotein and inhibit the proliferation of leukemia cells. However, specific histone deacetylase inhibitors can interrupt the effect of histone deacetylase to alleviate EVI1-mediated suppression of TGF-beta1/SMAD signaling. The tyrosine kinase inhibitor in the target therapy of chronic myeloid leukemia can effectively inhibit the tyrosine kinase activity of Bcr-Abl and induce suppression on the TGF-beta1/SMAD signaling pathway. The TGF-beta1/SMAD signaling pathway plays an important role in chronic myeloid leukemia cells and leads the leukemia cells to growth inhibition, differentiation and apoptosis. The positive influence of the TGF-beta1/SMAD signaling pathway in chronic myeloid leukemia is fairly significant, and its potential effects in clinical treatment will bring about definite benefits. Since it is a complex signaling pathway widely involved in many aspects of cellular activities, further study and comprehensive analysis of the TGF-beta1/SMAD signaling pathway are imperative and will have a guiding significance in research and clinical applications. It is an exciting area for future research.
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PMID:The transforming growth factor beta 1/SMAD signaling pathway involved in human chronic myeloid leukemia. 2130 8


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