Abstract
Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. MDS is also a susceptibility to acute myeloid leukemia (AML) and shown to be extremely resistant to current therapeutic strategies. MDS in a subset of 10-20% of patients arise after previous chemotherapy or radiation exposure for other malignancies. Because MDS is a heterogeneous disorder, specific gene abnormalities playing a role in the myelodysplastic process have been difficult to identify. Cytogenetic abnormalities are seen in half of MDS patients, and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations are rare. Genes more frequently implicated in the pathogenesis of MDS remain unknown. Although point mutations of critical genes have been demonstrated to contribute to the development MDS, there was no strong correlation between these mutations and clinical features. Recently, we reported the high incidence of somatic mutations in the AML1/RUNX1 gene, which is a critical regulator of definitive hematopoiesis and the most frequent target for translocation of AML, in MDS, especially refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt) and AML following MDS (defined here as MDS/AML). The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most of AML1/RUNX1 mutants lose trans-activation potential, which leads to a loss of AML1 function indicating that AML1/RUNX1 dysfunction is one of the major pathogenesis of MDS/AML. Normalizing AML1 function or regulating cooperative gene mutations would provide an important clue for molecular target therapies.
Keywords: Myelodysplastic syndrome (MDS), AML1/RUNX1, MDS/AML, genomic instability, Runt domain, FPD/AML, secondary MDS/AML
Current Cancer Drug Targets
Title: Implications of Somatic Mutations in the AML1/RUNX1 Gene in Myelodysplastic Syndrome (MDS): Future Molecular Therapeutic Directions for MDS
Volume: 6 Issue: 6
Author(s): Hironori Harada, Yuka Harada and Akiro Kimura
Affiliation:
Keywords: Myelodysplastic syndrome (MDS), AML1/RUNX1, MDS/AML, genomic instability, Runt domain, FPD/AML, secondary MDS/AML
Abstract: Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. MDS is also a susceptibility to acute myeloid leukemia (AML) and shown to be extremely resistant to current therapeutic strategies. MDS in a subset of 10-20% of patients arise after previous chemotherapy or radiation exposure for other malignancies. Because MDS is a heterogeneous disorder, specific gene abnormalities playing a role in the myelodysplastic process have been difficult to identify. Cytogenetic abnormalities are seen in half of MDS patients, and generally consist of partial or complete chromosome deletion or addition, whereas balanced translocations are rare. Genes more frequently implicated in the pathogenesis of MDS remain unknown. Although point mutations of critical genes have been demonstrated to contribute to the development MDS, there was no strong correlation between these mutations and clinical features. Recently, we reported the high incidence of somatic mutations in the AML1/RUNX1 gene, which is a critical regulator of definitive hematopoiesis and the most frequent target for translocation of AML, in MDS, especially refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt) and AML following MDS (defined here as MDS/AML). The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most of AML1/RUNX1 mutants lose trans-activation potential, which leads to a loss of AML1 function indicating that AML1/RUNX1 dysfunction is one of the major pathogenesis of MDS/AML. Normalizing AML1 function or regulating cooperative gene mutations would provide an important clue for molecular target therapies.
Export Options
About this article
Cite this article as:
Harada Hironori, Harada Yuka and Kimura Akiro, Implications of Somatic Mutations in the AML1/RUNX1 Gene in Myelodysplastic Syndrome (MDS): Future Molecular Therapeutic Directions for MDS, Current Cancer Drug Targets 2006; 6 (6) . https://dx.doi.org/10.2174/156800906778194595
DOI https://dx.doi.org/10.2174/156800906778194595 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- 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
Related Articles
-
Stimuli-responsive Smart Liposomes in Cancer Targeting
Current Drug Targets DNA Drug Design for Cancer Therapy
Current Pharmaceutical Design Autophagy in Chronic Myeloid Leukaemia: Stem Cell Survival and Implication in Therapy
Current Cancer Drug Targets Adeno-Associated Virus-Mediated Gene Transfer in Hematopoietic Stem/Progenitor Cells as a Therapeutic Tool
Current Gene Therapy Royal Jelly Acid, 10-Hydroxy-trans-2-Decenoic Acid, as a Modulator of the Innate Immune Responses
Endocrine, Metabolic & Immune Disorders - Drug Targets Cytokines as Novel Therapeutic Agents for Neuroinflammatory Disorders: A Role for Interferon-β in the Treatment of Multiple Sclerosis
Current Medicinal Chemistry - Central Nervous System Agents Promoters and Control Elements: Designing Expression Cassettes for Gene Therapy
Current Gene Therapy A Review of Pharmacological Treatment Options for Lung Cancer: Emphasis on Novel Nanotherapeutics and Associated Toxicity
Current Drug Targets Treatment of Relapsed Acute Myeloid Leukaemia
Reviews on Recent Clinical Trials Targeting Aurora Kinases in Cancer Treatment
Current Drug Targets DTCM-Glutarimide Hinders Growth of Childhood Leukemia Cells but Fails to Improve the Efficacy of Commonly Used Chemotherapeutic Agents
Current Bioactive Compounds Protein Interaction Domains: Structural Features and Drug Discovery Applications (Part 2)
Current Medicinal Chemistry Studies on Non-synonymous Polymorphisms Altering Human DNA Topoisomerase II-Alpha Interaction with Amsacrine and Mitoxantrone: An <i>In Silico</i> Approach
Current Cancer Drug Targets Machine Learning for Childhood Acute Lymphoblastic Leukaemia Gene Expression Data Analysis: A Review
Current Bioinformatics Patent Selections
Recent Patents on Anti-Infective Drug Discovery Recent Advances in Epitope Design for Immunotherapy of Cancer
Recent Patents on Anti-Cancer Drug Discovery Brain Tumor Causes, Symptoms, Diagnosis and Radiotherapy Treatment
Current Medical Imaging HDAC as a Therapeutic Target for Treatment of Endometrial Cancers
Current Pharmaceutical Design Plasticity and Therapeutic Potential of Mesenchymal Stem Cells in the Nervous System
Current Pharmaceutical Design Synthesis and β-Glucuronidase Inhibitory Potential of Benzimidazole Derivatives
Medicinal Chemistry