Abstract
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients’ lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): BCR-ABL1 that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of Bimmunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like ALL is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient’s specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors.
Keywords: ALL, hematologic malignancies, lymphoblastic leukemia, chemotherapy, kinase-activating genetic lesions.
Current Medicinal Chemistry
Title:Targeting Kinase-activating Genetic Lesions to Improve Therapy of Pediatric Acute Lymphoblastic Leukemia
Volume: 25 Issue: 24
Author(s): Raffaella Franca, Natasa K. Kuzelicki, Claudio Sorio, Eleonora Toffoletti, Oksana Montecchini, Alice Poropat, Marco Rabusin*, Debora Curci, Dino Paladin, Gabriele Stocco and Giuliana Decorti
Affiliation:
- Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste,Italy
Keywords: ALL, hematologic malignancies, lymphoblastic leukemia, chemotherapy, kinase-activating genetic lesions.
Abstract: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients’ lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): BCR-ABL1 that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of Bimmunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like ALL is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient’s specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors.
Export Options
About this article
Cite this article as:
Franca Raffaella , Kuzelicki K. Natasa , Sorio Claudio , Toffoletti Eleonora, Montecchini Oksana, Poropat Alice , Rabusin Marco *, Curci Debora, Paladin Dino, Stocco Gabriele and Decorti Giuliana , Targeting Kinase-activating Genetic Lesions to Improve Therapy of Pediatric Acute Lymphoblastic Leukemia, Current Medicinal Chemistry 2018; 25 (24) . https://dx.doi.org/10.2174/0929867324666170727101932
DOI https://dx.doi.org/10.2174/0929867324666170727101932 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
- Announcements
Related Articles
-
Cytotoxic Compounds in the Treatment of Castration-Resistant Prostate Cancer
Anti-Cancer Agents in Medicinal Chemistry Primary Tumors of the Sacrum: Imaging Findings
Current Medical Imaging Recent Advances in Pharmacokinetics of Polymeric Excipients Used in Nanosized Anti-Cancer Drugs
Current Drug Metabolism Serum N-terminal Pro-brain Natriuretic Peptide Level is Associated with the Development of Chronic Kidney Diseases in Patients with Type 2 Diabetes
Endocrine, Metabolic & Immune Disorders - Drug Targets Developments in Selective Small Molecule ATP-Targeting the Serine/Threonine Kinase Akt/PKB
Mini-Reviews in Medicinal Chemistry Graphical Abstracts:
Current Angiogenesis (Discontinued) Targeting of NF-kappaB Signaling Pathway, other Signaling Pathways and Epigenetics in Therapy of Multiple Myeloma
Cardiovascular & Hematological Disorders-Drug Targets Circumventing Melanoma Chemoresistance by Targeting DNA Repair
Current Medicinal Chemistry New Insights into Invasive Aspergillosis - from the Pathogen to the Disease
Current Pharmaceutical Design From Bacteria to Antineoplastic: Epothilones A Successful History
Anti-Cancer Agents in Medicinal Chemistry Identifying Molecular Biomarker for the Lung Squamous Cell Carcinoma by Integrating Multifactorial Data
Current Bioinformatics Dequalinium-Derived Nanoconstructs: A Promising Vehicle for Mitochondrial Targeting
Current Drug Delivery Combined Modality Therapy in Pancreatic Adenocarcinoma: Review and Updates on a Controversial Issue
Current Pharmaceutical Design On the Power of Additional and Complex Chromosomal Aberrations in CML
Current Genomics Biologic Therapy in Immune Mediated Inflammatory Disease: Basic Science and Clinical Concepts
Current Drug Safety A Stress Repair Mechanism That Maintains Vertebrate Structure During Stress
Cardiovascular & Hematological Disorders-Drug Targets Angiogenesis Inhibitors and Vascular Disrupting Agents in Non-Small Cell Lung Cancer
Current Medicinal Chemistry Targeted Pathways in Breast Cancer: Molecular and Protein Markers Guiding Therapeutic Decisions
Current Molecular Pharmacology Attacking c-Myc: Targeted and Combined Therapies for Cancer
Current Pharmaceutical Design Ruxolitinib Regulates the Autophagy Machinery in Multiple Myeloma Cells
Anti-Cancer Agents in Medicinal Chemistry