Mutational analysis in chronic myeloid leukemia: when and what to do?
ABSTRACT Imatinib, which was the first targeted therapy for patients with chronic myeloid leukemia (CML), has led to the significant prolongation of life for most patients. However, approximately 30% fail therapy. The major mechanism of acquired resistance is somatic mutation within the BCR-ABL1 kinase domain, which affects imatinib binding. Recently, more potent inhibitors have been approved that retain activity against most of the more than 100 mutations. However, some mutations remain problematic for one or more of the new inhibitors. The most frequently detected mutation, T315I, remains resistant to all of the currently approved inhibitors. More sensitive mutation techniques that focus on the detection of a limited number of specific mutations may be beneficial, but are yet to prove their clinical utility for the early detection of relapse in routine practice.
Inhibitors with alternate binding modes that may overcome T315I-associated resistance are at the preclinical stage or are undergoing clinical trial.
Each of the new, more potent kinase inhibitor drugs appear to have a partially overlapping set of mutations that confer a degree of resistance. Mutation detection techniques may need to adapt to provide clinicians with a more timely indication of mutation acquisition and pending relapse.
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ABSTRACT: Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.British Journal of Haematology 06/2014; 167(1). DOI:10.1111/bjh.12977 · 4.96 Impact Factor
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ABSTRACT: There are important breakthroughs in the treatment of paediatric acute lymphoblastic leukaemia (ALL) since 1950, by which the prognosis of the child majority suffered from ALL has been improved. However, there are urgent needs to have disease-specific biomarkers to monitor the therapeutic efficacy and predict the patient prognosis. The present study overviewed proteomics-based research on paediatric ALL to discuss important advances to combat cancer cells and search novel and real protein biomarkers of resistance or sensitivity to drugs which target the signalling networks. We highlighted the importance and significance of a proper phospho-quantitative design and strategy for paediatric ALL between relapse and remission, when human body fluids from cerebrospinal, peripheral blood, or bone-marrow were applied. The present article also assessed the schedule for the analysis of body fluids from patients at different states, importance of proteomics-based tools to discover ALL-specific and sensitive biomarkers, to stimulate paediatric ALL research via proteomics to 'build' the reference map of the signalling networks from leukemic cells at relapse, and to monitor significant clinical therapies for ALL-relapse.Journal of Cellular and Molecular Medicine 06/2014; DOI:10.1111/jcmm.12319 · 3.70 Impact Factor
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ABSTRACT: Purpose The clinical outcome of chronic myeloid leukemia (CML) patients has been changed dramatically due to the development of imatinib (IM). However, the emergence of IM resistance, commonly associated with point mutations within the BCR-ABL kinase domain, remains a major clinical problem. Here, we investigated the effects of E35, a novel derivative of emodin, on the IM-resistant 32Dp210-T315I cells. Methods Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and colony formation assay. Induction of apoptosis was confirmed by DNA fragmentation assay and annexin V/PI staining assay. Real-time quantitative PCR was used to access the BCR-ABL gene expression. Changes of related signaling molecules were detected through Western blot. Results E35 was found to potently inhibit proliferation of 32Dp210-T315I cells with an average IC50 of 2.4 µM at 48 h. Colony formation was almost fully suppressed in 1.0 μM E35 group. DNA fragmentation and annexin V/PI staining assay exhibited the typical DNA fragmentation and the increased proportion of early apoptotic cells, respectively. The induction of apoptosis was associated with increase of Bax to Bcl-2 expression ratio and activation of caspase cascades involving decrease of pro-caspase 9 and pro-caspase 3 and increase of PARP cleavage. The protein expression of P210BCR-ABL and p-P210BCR-ABL was down-regulated in the presence of E35, although the mRNA levels remained almost unchanged. Moreover, the activation of the P210BCR-ABL downstream signaling pathways including CrkL, Akt/mTOR and MEK/ERK was fully suppressed by E35. Conclusion Our study indicated that E35 might be a potential antileukemia agent against IM resistance in CML.Journal of Cancer Research and Clinical Oncology 09/2014; 141(2). DOI:10.1007/s00432-014-1820-2 · 3.01 Impact Factor