Abstract
Chronic myelogenous leukemia (CML) is a hematological malignancy that is characteristic by as expansion of myeloid cells and their premature release into the circulation. The molecular cause of CML is the fusion oncoprotein Bcr- Abl whose constitutive tyrosine-kinase (TK) activity maintains enhanced signaling through multiple signal transduction pathways and confers proliferative and survival advantage to CML cells. These effects can be largely suppressed by TK inhibitor Imatinib mesylate, currently the leading drug in CML treatment. However, Bcr-Abl contains also additional functional domains, in particular a DBL homology (DH) domain with guanine-exchange function (GEF) which can activate small GTPases of Rho family and a Src-homology3 (SH3) domain which recruits other proteins with GEF activity. Bcr-Abl affects among others the RhoA/ROCK/LIM/cofilin pathway that regulates the actin cytoskeleton assembly and thereby the cellular adhesion and migration. This review deals in detail with the known points of interference between Bcr-Abl and Rho kinase pathways and with the effects of Imatinib mesylate on Rho signaling and cell adhesion to the extracellular matrix (ECM) components. The potential protein targets related to Bcr-Abl non-kinase activity are discussed.
Keywords: CML, Bcr-Abl, Rho GTPase, adhesion
Cardiovascular & Hematological Disorders-Drug Targets
Title: Rho-Signaling Pathways in Chronic Myelogenous Leukemia
Volume: 8 Issue: 4
Author(s): Katerina Kuzelova and Zbynek Hrkal
Affiliation:
Keywords: CML, Bcr-Abl, Rho GTPase, adhesion
Abstract: Chronic myelogenous leukemia (CML) is a hematological malignancy that is characteristic by as expansion of myeloid cells and their premature release into the circulation. The molecular cause of CML is the fusion oncoprotein Bcr- Abl whose constitutive tyrosine-kinase (TK) activity maintains enhanced signaling through multiple signal transduction pathways and confers proliferative and survival advantage to CML cells. These effects can be largely suppressed by TK inhibitor Imatinib mesylate, currently the leading drug in CML treatment. However, Bcr-Abl contains also additional functional domains, in particular a DBL homology (DH) domain with guanine-exchange function (GEF) which can activate small GTPases of Rho family and a Src-homology3 (SH3) domain which recruits other proteins with GEF activity. Bcr-Abl affects among others the RhoA/ROCK/LIM/cofilin pathway that regulates the actin cytoskeleton assembly and thereby the cellular adhesion and migration. This review deals in detail with the known points of interference between Bcr-Abl and Rho kinase pathways and with the effects of Imatinib mesylate on Rho signaling and cell adhesion to the extracellular matrix (ECM) components. The potential protein targets related to Bcr-Abl non-kinase activity are discussed.
Export Options
About this article
Cite this article as:
Kuzelova Katerina and Hrkal Zbynek, Rho-Signaling Pathways in Chronic Myelogenous Leukemia, Cardiovascular & Hematological Disorders-Drug Targets 2008; 8 (4) . https://dx.doi.org/10.2174/187152908786786241
DOI https://dx.doi.org/10.2174/187152908786786241 |
Print ISSN 1871-529X |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-4063 |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Using Nutrigenomics to Evaluate Apoptosis as a Preemptive Target in Cancer Prevention
Current Cancer Drug Targets Galectins: Major Signaling Modulators Inside and Outside the Cell
Current Molecular Medicine Clostridium difficile Infection: Associations with Chemotherapy, Radiation Therapy, and Targeting Therapy Treatments
Current Medicinal Chemistry Refractory Chronic Lymphocytic Leukemia: A Therapeutic Challenge
Current Cancer Drug Targets Cancer/Testis Antigens Trigger Epithelial-Mesenchymal Transition and Genesis of Cancer Stem-Like Cells
Current Pharmaceutical Design Novel Therapeutic Approaches Based on the Targeting of Microenvironment-Derived Survival Pathways in Human Cancer: Experimental Models and Translational Issues
Current Pharmaceutical Design TNF-Related Apoptosis-Inducing Ligand (TRAIL): A Potential Candidate for Combined Treatment of Hematological Malignancies
Current Pharmaceutical Design ChemoImmunoModulation: Immune Regulation by the Antineoplastic Chemotherapeutic Agents
Current Medicinal Chemistry Metabolism of the Novel IMP Dehydrogenase Inhibitor Benzamide Riboside
Medicinal Chemistry Reviews - Online (Discontinued) Pancreatic Cancer and Personalized Medicine: Can Genomics Facilitate Early Diagnosis or Improve Therapeutic Outcomes?
Current Pharmacogenomics and Personalized Medicine Signal Transduction Therapy with Rationally Designed Kinase Inhibitors
Current Signal Transduction Therapy Targeting RAS Signaling Pathways in Juvenile Myelomonocytic Leukemia
Current Drug Targets Replicative Oncolytic Herpes Simplex Viruses in Combination Cancer Therapies
Current Gene Therapy NF-κB Inhibitors in Head and Neck Cancer
Letters in Drug Design & Discovery Clinical and Genetic Features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome
Current Molecular Medicine Genetics, Gene Expression, and Targeted Therapies in Chronic Lymphocytic Leukemia
Current Drug Targets Reduced-Intensity Stem Cell Transplantation for Hematological Malignancies: Current Status and the Future
Current Stem Cell Research & Therapy Proteomics to Study Candida albicans Biology and Pathogenicity
Infectious Disorders - Drug Targets Combining Gene Therapy and Radiation Against Cancer
Current Gene Therapy Momordica balsamina: A Medicinal and Neutraceutical Plant for Health Care Management
Current Pharmaceutical Biotechnology