Management of the advanced phases of chronic myelogenous leukemia in the era of tyrosine kinase inhibitors

Martin, Mike G.; DiPersio, John F.; Uy, Geoffrey L.

doi:10.1080/10428190802517765

Cited by 10 publications

(7 citation statements)

References 71 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This goal was confirmed through both computational modeling and in vitro experiments. Alternative treatments for CML are still needed because of the inability to eliminate CML stem cells, resistance to small molecule inhibitors, and ineffective treatment of advanced stages of the disease (25,(52)(53)(54)(55). Given the importance the coiled coil domain has in the regulation of Bcr-Abl activity, it has long been hypothesized that this domain could be used therapeutically.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Dixon

Pendley

Bruno

et al. 2011

Journal of Biological Chemistry

105

View full text Add to dashboard Cite

Oligomerization is an important regulatory mechanism for many proteins, including oncoproteins and other pathogenic proteins. The oncoprotein Bcr-Abl relies on oligomerization via its coiled coil domain for its kinase activity, suggesting that a designed coiled coil domain with enhanced binding to Bcr-Abl and reduced self-oligomerization would be therapeutically useful. Key mutations in the coiled coil domain of Bcr-Abl were identified that reduce homo-oligomerization through intermolecular charge-charge repulsion yet increase interaction with the Bcr-Abl coiled coil through additional salt bridges, resulting in an enhanced ability to disrupt the oligomeric state of Bcr-Abl. The mutations were modeled computationally to optimize the design. Assays performed in vitro confirmed the validity and functionality of the optimal mutations, which were found to exhibit reduced homo-oligomerization and increased binding to the Bcr-Abl coiled coil domain. Introduction of the mutant coiled coil into K562 cells resulted in decreased phosphorylation of Bcr-Abl, reduced cell proliferation, and increased caspase-3/7 activity and DNA segmentation. Importantly, the mutant coiled coil domain was more efficacious than the wild type in all experiments performed. The improved inhibition of Bcr-Abl through oligomeric disruption resulting from this modified coiled coil domain represents a viable alternative to small molecule inhibitors for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Dixon

Pendley

Bruno

et al. 2011

Journal of Biological Chemistry

105

View full text Add to dashboard Cite

show abstract

“…Treatment modalities that are effective in treating CML-CP, such as TKI therapy and stem cell transplantation, achieve lower rates of response and survival rates when used to treat CML-AP/BC. 33,34 Furthermore, stem cell transplantation is associated with high morbidity, so its application is generally restricted to patients under 65 years of age. 30 Because advanced CML poses therapeutic challenges, the stable maintenance of patients in CML-CP has emerged as an overarching goal of modern CML management.…”

Section: Tki Therapy Lowers the Rate Of Disease Progression To Ap/bcmentioning

confidence: 99%

Ensuring optimal adherence to BCR-ABL1 tyrosine kinase inhibitor therapy for chronic myeloid leukemia

Welch¹,

Kaled²

2013

Community Oncol

View full text Add to dashboard Cite

The advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) has dramatically changed the management of patients with CML. With continuous long-term TKI therapy, CML can be managed like a chronic condition, and most patients can expect to have a normal life expectancy. Given the prospect of lifelong therapy, however, issues related to adherence become particularly important and warrant greater attention since attainment of favorable long-term survival depends in large part on consistent, appropriate treatment administration over years, if not decades. As the multidisciplinary care team approach to cancer care has gained traction at academic centers and community practices, midlevel providers, including nurse practitioners and physician assistants, have taken on greater patient-related responsibilities. Midlevel providers have the potential to foster and maintain meaningful provider-patient relationships that may span years, and are well positioned to recognize and manage problems that patients may have with adherence. Here we discuss the importance of achieving and maintaining responses to TKI therapy, describe the clinical consequences of poor adherence to TKI therapy in CML, and outline factors behind poor adherence. We also share strategies that we use at our center to improve adherence to long-term TKI therapy for CML.

show abstract

“…Diverse abnormal chromosomal structures have been detected including; translocations, duplications, deletions, inversions, fusion, double minute chromosomes, chromosomal breaks, sister chromatid exchange (SCE), apoptotic bodies, and defective mitotic figures [3,4], but shared chromosomal aberrations have received the most attention [5,6]. Identification of recurrent chromosomal markers in patients has greatly contributed to both diagnosis and patient management, particularly in certain types of blood cancers with dominant recurrent changes [7]. …”

Section: Introductionmentioning

confidence: 99%

Comparison of mitotic cell death by chromosome fragmentation to premature chromosome condensation

et al. 2010

View full text Add to dashboard Cite

Mitotic cell death is an important form of cell death, particularly in cancer. Chromosome fragmentation is a major form of mitotic cell death which is identifiable during common cytogenetic analysis by its unique phenotype of progressively degraded chromosomes. This morphology however, can appear similar to the morphology of premature chromosome condensation (PCC) and thus, PCC has been at times confused with chromosome fragmentation. In this analysis the phenomena of chromosome fragmentation and PCC are reviewed and their similarities and differences are discussed in order to facilitate differentiation of the similar morphologies. Furthermore, chromosome pulverization, which has been used almost synonymously with PCC, is re-examined. Interestingly, many past reports of chromosome pulverization are identified here as chromosome fragmentation and not PCC. These reports describe broad ranging mechanisms of pulverization induction and agree with recent evidence showing chromosome fragmentation is a cellular response to stress. Finally, biological aspects of chromosome fragmentation are discussed, including its application as one form of non-clonal chromosome aberration (NCCA), the driving force of cancer evolution.

show abstract

Management of the advanced phases of chronic myelogenous leukemia in the era of tyrosine kinase inhibitors

Cited by 10 publications

References 71 publications

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Ensuring optimal adherence to BCR-ABL1 tyrosine kinase inhibitor therapy for chronic myeloid leukemia

Comparison of mitotic cell death by chromosome fragmentation to premature chromosome condensation

Contact Info

Product

Resources

About