The impact of the BCR-ABL oncogene in the pathology and treatment of chronic myeloid leukemia

El-Tanani, Mohamed; Nsairat, Hamdi; Matalka, Ismail I.; Lee, Yin Fai; Rizzo, Manfredi; Aljabali, Alaa A.; Mishra, Vijay; Mishra, Yachana; Hromić-Jahjefendić, Altijana; Tambuwala, Murtaza M.

doi:10.1016/j.prp.2024.155161

Cited by 7 publications

(2 citation statements)

References 136 publications

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“…Imatinib (also known as "Gleevec" or "Glivec") is a tyrosine kinase inhibitor and was called the "magic bullet" when it revolutionized the treatment of chronic myeloid leukemia (CML) in 2001 [105,106]. The disease is caused by a genetic change known as the Philadelphia chromosome or the bcr-abl gene, which produces hyperactive BCR/ABL proteins [107,108].…”

Section: Tyrosine Kinases Inhibitorsmentioning

confidence: 99%

Historical Perspective and Current Trends in Anticancer Drug Development

Gach-Janczak,

Drogosz-Stachowicz,

Janecka

et al. 2024

Cancers

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Cancer is considered one of the leading causes of death in the 21st century. The intensive search for new anticancer drugs has been actively pursued by chemists and pharmacologists for decades, focusing either on the isolation of compounds with cytotoxic properties from plants or on screening thousands of synthetic molecules. Compounds that could potentially become candidates for new anticancer drugs must have the ability to inhibit proliferation and/or induce apoptosis in cancer cells without causing too much damage to normal cells. Some anticancer compounds were discovered by accident, others as a result of long-term research. In this review, we have presented a brief history of the development of the most important groups of anticancer drugs, pointing to the fact that they all have many side effects.

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Section: Tyrosine Kinases Inhibitorsmentioning

confidence: 99%

Historical Perspective and Current Trends in Anticancer Drug Development

Gach-Janczak,

Drogosz-Stachowicz,

Janecka

et al. 2024

Cancers

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“…This event fuses the BCR gene on chromosome 22 with the ABL gene on chromosome 9 (BCR::ABL), causing constitutive activation of the ABL kinase, which promotes cell division. Although three different BCR-ABL fusion recombination events have been identified, they all have the effect of removing an N-terminal Abl1 region and replacing it with the serine/threonine kinase domain of BCR [11,12]. This affects an intramolecular interaction within the Abl1 protein required for self-inhibition [13].…”

Section: Introductionmentioning

confidence: 99%

Multi-Omics Integration for Liver Cancer Using Regression Analysis

Raj,

Petreaca,

Mirzaei

2024

CIMB

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Genetic biomarkers have played a pivotal role in the classification, prognostication, and guidance of clinical cancer therapies. Large-scale and multi-dimensional analyses of entire cancer genomes, as exemplified by projects like The Cancer Genome Atlas (TCGA), have yielded an extensive repository of data that holds the potential to unveil the underlying biology of these malignancies. Mutations stand out as the principal catalysts of cellular transformation. Nonetheless, other global genomic processes, such as alterations in gene expression and chromosomal re-arrangements, also play crucial roles in conferring cellular immortality. The incorporation of multi-omics data specific to cancer has demonstrated the capacity to enhance our comprehension of the molecular mechanisms underpinning carcinogenesis. This report elucidates how the integration of comprehensive data on methylation, gene expression, and copy number variations can effectively facilitate the unsupervised clustering of cancer samples. We have identified regressors that can effectively classify tumor and normal samples with an optimal integration of RNA sequencing, DNA methylation, and copy number variation while also achieving significant p-values. Further, these regressors were trained using linear and logistic regression with k-means clustering. For comparison, we employed autoencoder- and stacking-based omics integration and computed silhouette scores to evaluate the clusters. The proof of concept is illustrated using liver cancer data. Our analysis serves to underscore the feasibility of unsupervised cancer classification by considering genetic markers beyond mutations, thereby emphasizing the clinical relevance of additional global cellular parameters that contribute to the transformative process in cells. This work is clinically relevant because changes in gene expression and genomic re-arrangements have been shown to be signatures of cellular transformation across cancers, as well as in liver cancers.

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Structure‐Guided Drug Design Targeting Abl Kinase: How Structure and Regulation Can Assist in Designing New Drugs

Martins.,

Fernandes,

Vieira

et al. 2024

ChemBioChem

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The human protein Abelson kinase (Abl), a tyrosine kinase, plays a pivotal role in developing chronic myeloid leukemia (CML). Abl's involvement in various signaling pathways underscores its significance in regulating fundamental biological processes, including DNA damage responses, actin polymerization, and chromatin structural changes. The discovery of the Bcr‐Abl oncoprotein, resulting from a chromosomal translocation in CML patients, revolutionized the understanding and treatment of the disease. The introduction of targeted therapies, starting with interferon‐alpha and culminating in the development of tyrosine kinase inhibitors (TKIs) like imatinib, significantly improved patient outcomes. However, challenges such as drug resistance and side effects persist, indicating the necessity of research into novel therapeutic strategies. This review describes advancements in Abl kinase inhibitor development, emphasizing rational compound design from structural and regulatory information. Strategies, including bivalent inhibitors, PROTACs, and compounds targeting regulatory domains, promise to overcome resistance and minimize side effects. Additionally, leveraging the intricate structure and interactions of Bcr‐Abl may provide insights into developing inhibitors for other kinases. Overall, this review highlights the importance of continued research into Abl kinase inhibition and its broader implications for therapeutic interventions targeting kinase‐driven diseases. It provides valuable insights and strategies that may guide the development of next‐generation therapies.

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The impact of the BCR-ABL oncogene in the pathology and treatment of chronic myeloid leukemia

Cited by 7 publications

References 136 publications

Historical Perspective and Current Trends in Anticancer Drug Development

Historical Perspective and Current Trends in Anticancer Drug Development

Multi-Omics Integration for Liver Cancer Using Regression Analysis

Structure‐Guided Drug Design Targeting Abl Kinase: How Structure and Regulation Can Assist in Designing New Drugs

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