Natural course and biology of CML

Chereda, Bradley; Melo, Junia V.

doi:10.1007/s00277-015-2325-z

Cited by 181 publications

(147 citation statements)

References 180 publications

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“…30 ABL1 is a nonreceptor tyrosine kinase that is involved in regulation of multiple cellular processes, including cell division. 31 ABL1 normally shuttles between the cytoplasm and nucleus; however, when fused with BCR (breakpoint cluster region protein), the ABL1 kinase is constitutively activated and becomes retained in the cytoplasm.…”

Section: Tyrosine Kinase Inhibitors Targeting Ablmentioning

confidence: 99%

The influence of subclonal resistance mutations on targeted cancer therapy

2015

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Clinical oncology is being revolutionized by the increasing use of molecularly targeted therapies. This paradigm holds great promise for improving cancer treatment; however, allocating specific therapies to the patients who are most likely to derive a durable benefit continues to represent a considerable challenge. It is becoming increasingly clear that cancers are characterized by extensive intratumour genetic heterogeneity, and that patients being considered for treatment with a targeted agent might, therefore, already possess resistance to the drug in a minority of cells. Indeed, multiple examples of pre-existing subclonal resistance mutations to various molecularly targeted agents have been described, which we review herein. Early detection of pre-existing or emerging drug resistance could enable more personalized use of targeted cancer therapy, as patients could be stratified to receive the therapies that are most likely to be effective. We consider how monitoring of drug resistance could be incorporated into clinical practice to optimize the use of targeted therapies in individual patients.

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Section: Tyrosine Kinase Inhibitors Targeting Ablmentioning

confidence: 99%

The influence of subclonal resistance mutations on targeted cancer therapy

2015

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“…Approximately 95% of the cases are characterized by clonal expansion of myeloid cells containing the Philadelphia chromosome [1, 2] which has a translocation of chromosomes 9 and 22 t(9;22), producing a fusion between the BCR and ABL genes [3]. The resultant BCR-ABL hybrid protein is a constitutively active tyrosine kinase that functions as an oncoprotein; consequently, it activates several important signal transduction pathways involved in cell growth inhibition of cellular differentiation and programmed cell death [4]. Although, several tyrosine kinase inhibitors targeting the BCR-ABL hybrid have been developed and shown to be successful for chronic myeloid leukemia treatment, leukemia cells can become resistant to treatment [5].…”

Section: Introductionmentioning

confidence: 99%

A Subpopulation of the K562 Cells Are Killed by Curcumin Treatment after G2/M Arrest and Mitotic Catastrophe

et al. 2016

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Curcumin is extensively investigated as a good chemo-preventive agent in the development of many cancers and particularly in leukemia, including treatment of chronic myelogenous leukemia and it has been proposed as an adjuvant for leukemia therapies. Human chronic myeloid leukemia cells (K562), were treated with 20 μM of curcumin, and we found that a subpopulation of these cells were arrested and accumulate in the G2/M phase of the cell cycle. Characterization of this cell subpopulation showed that the arrested cells presented nuclear morphology changes resembling those described for mitotic catastrophe. Mitotic cells displayed abnormal chromatin organization, collapse of the mitotic spindle and abnormal chromosome segregation. Then, these cells died in an apoptosis dependent manner and showed diminution in the protein levels of BCL-2 and XIAP. Moreover, our results shown that a transient activation of the nuclear factor κB (NFκB) occurred early in these cells, but decreased after 6 h of the treatment, explaining in part the diminution of the anti-apoptotic proteins. Additionally, P73 was translocated to the cell nuclei, because the expression of the C/EBPα, a cognate repressor of the P73 gene, was decreased, suggesting that apoptosis is trigger by elevation of P73 protein levels acting in concert with the diminution of the two anti-apoptotic molecules. In summary, curcumin treatment might produce a P73-dependent apoptotic cell death in chronic myelogenous leukemia cells (K562), which was triggered by mitotic catastrophe, due to sustained BAX and survivin expression and impairment of the anti-apoptotic proteins BCL-2 and XIAP.

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“…Clinical resistance to IM for CML patients has been attributed to several mechanisms, and the dominant mechanism appears to be the acquisition of point mutations in the ABL kinase domain (KD) (30%-90% of patients de-velop resistance) that lead to altered affinity for IM by the BCR-ABL1 protein [6,7]. However, due to IM treatment resistance, a proportion of CML patients easily progress to blast crisis phase (blastic transformation may be myeloid, lymphoid, or undifferentiated/mixed), which is an advanced stage of CML disease progression that contributes to the expansion of primitive cells and not mature granulocytes [8][9][10]. To date, greater than 90 ABL gene mutants have been described [6,11].…”

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confidence: 99%

Characteristics of the TCR Vβ repertoire in imatinib-resistant chronic myeloid leukemia patients with ABL mutations

Lai

et al. 2015

Sci. China Life Sci.

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Diversity in the T cell receptor (TCR) repertoire provides a miniature defense ability for the T cell immune system that may be related to tumor initiation and progression. Understanding the T cell immune status of leukemia patients is critical for establishing specific immunotherapies. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR V T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR V repertoire in 4 cases with imatinib-resistant CML in blast crisis (BC-CML) with abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase domain mutations (KDMs). Examination of TCR V expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) and GeneScan analysis. Significantly skewed TCR V repertoires were observed in BC-CML patients with different KDMs, and 4 to 8 oligoclonally expanded TCR V subfamilies could be identified in each sample. Intriguingly, a relatively highly expanded V9 clone with the same length as complementarity-determining region 3 (CDR3) (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the only CML patient in myeloid blast crisis (MBC-CML). In conclusion, restricted TCR V repertoire expression and decreased clone complexity was a general phenomenon observed in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency of these patients. In addition, clonally expanded V9 T cell clones may indicate a specific immune response to leukemia-associated antigens in LBC-CML patients.T cell repertoire, chronic myeloid leukemia, blast crisis, imatinib resistance, BCR-ABL mutation Citation:

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Natural course and biology of CML

Cited by 181 publications

References 180 publications

The influence of subclonal resistance mutations on targeted cancer therapy

The influence of subclonal resistance mutations on targeted cancer therapy

A Subpopulation of the K562 Cells Are Killed by Curcumin Treatment after G2/M Arrest and Mitotic Catastrophe

Characteristics of the TCR Vβ repertoire in imatinib-resistant chronic myeloid leukemia patients with ABL mutations

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