Chronic Myelogenous Leukemia: From Molecular Biology to Clinical Aspects and Novel Targeted Therapies

Inokuchi, Koiti

doi:10.1272/jnms.73.178

Cited by 8 publications

(9 citation statements)

References 76 publications

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“…However, the break in the BCR gene just distal to the first exon of BCR, in a region named for the minor breakpoint cluster region (m-bcr), is mainly associated with Ph-positive acute lymphoblastic leukemia (ALL). Consequently, BCR-ABL proteins are approximately 190, 210, and 230 kD, and the fusion protein in human CML is approximately 210 kD [2,9,10].…”

Section: Introduction-chronic Myeloid Leukemiamentioning

confidence: 99%

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An overview of chronic myeloid leukemia and its animal models

Chen

et al. 2015

Sci. China Life Sci.

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Chronic myeloid leukemia (CML) is a form of leukemia characterized by the presence of clonal bone marrow stem cells with the proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors. CML is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia (Ph) chromosome or t (9;22) translocation (BCR-ABL). CML is now usually treated with targeted drugs called tyrosine kinase inhibitors (TKIs). The mechanism and natural history of CML is still unclear. Here, we summarize the present CML animal disease models and compare them with each other. Meanwhile, we propose that it is a very wise choice to establish zebrafish (Danio rerio) CML model mimics clinical CML. This model could be used to learn more about the mechanism of CML, and to aid in the development of new drugs to treat CML. chronic myeloid leukemia (CML), animal disease model, zebrafish Citation:Ma WX, Ma N, Chen XH, Zhang YY, Zhang WQ. An overview of chronic myeloid leukemia and its animal models.

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Section: Introduction-chronic Myeloid Leukemiamentioning

confidence: 99%

“…Many molecular signaling pathways essential to the pathogenesis of chronic leukemia have been found to be downstream of the BCR-ABL protein [8,10]. The BCR-ABL fusion protein can promote cell proliferation and increase anti-apoptosis, activating key signal molecules/ pathways.…”

Section: Introduction-chronic Myeloid Leukemiamentioning

confidence: 99%

An overview of chronic myeloid leukemia and its animal models

Chen

et al. 2015

Sci. China Life Sci.

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“…Chronic myeloid leukemia (CML) was first noticed in 1845 by Inokuchi,1 who realized that the disease originated in the bone marrow and used the term “myeloid leukemia.” However, the pathogenesis of the disease was only understood in 1960 when Nowell and Hungerford discovered the major cause of CML, the Philadelphia (Ph) chromosome, and its relation to CML development 2. In their study, Nowell and Hungerford compared leukemia cells from chronic phase CML patients with the cells from other leukemias, and they found that the leukemic cells of chronic phase CML patients had a minute chromosome “abnormality” which was named the Philadelphia chromosome 3.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike ABL which is located in the nucleus and expressed when needed, BCR-ABL fusion protein is localized in the cytoplasm of Ph+ cells and has constitutive tyrosine kinase activity without any regulation 6. BCR-ABL kinase includes several different domains with important functions, such as coiled-coil motif (oligomerization domain); the tyrosine 177 (Grb-2 binding site) and rho-GEF domains on the BCR portion; and the regulatory Src homology (SH) regions SH3 and SH2, the SH1 (tyrosine kinase domain), the nuclear localization domain, DNA-binding domain, and actin-binding domain on the ABL portion 1,7. BCR-ABL activates many intracellular signaling pathways that are responsible for proliferation, genetic instability, suppression of apoptosis, and weakening of cellular adhesion 8,9.…”

Section: Introductionmentioning

confidence: 99%

“…BCR-ABL activates many intracellular signaling pathways that are responsible for proliferation, genetic instability, suppression of apoptosis, and weakening of cellular adhesion 8,9. The most important pathways involved in BCR-ABL-mediated CML are Ras, STAT, PI3-K/Akt, NFκB, and Myc 1. Pendergast et al10 showed the role of the tyrosine 177 domain of BCR-ABL in BCR-ABL-induced oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia

Baran¹,

Saydam²

2012

JBM

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Chronic myeloid leukemia (CML) is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+) chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs) exerting their effect against the oncogenic breakpoint cluster region (BCR)-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients compared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.

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Dup-697, a specific COX-2 inhibitor, suppresses growth and induces apoptosis on K562 leukemia cells by cell-cycle arrest and caspase-8 activation

et al. 2007

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This investigation was designed to assess the effect of DuP-697 on growth and apoptosis in a human chronic myeloid leukemia (CML) cell line (K562 cells) and primary CML cells from CML patient bone marrow. DuP-697 significantly suppressed K562 cells and primary CML cells growth and induced apoptosis in a concentration-dependent manner and the growth-inhibiting effect was independent on Philadelphia chromosome. The IC50 of DuP-697 at 36 h was 31.7 muM. It arrested G1-S phase transmit on cell cycle and its apoptosis activity was partially abrogated by pretreating K562 cells with Z-IETD-fmk, a specific inhibitor of caspase-8. This study suggested that Dup-697 suppresses growth and induces apoptosis on K562 leukemia cells by cell-cycle arrest and caspase-8 activation.

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Chronic Myelogenous Leukemia: From Molecular Biology to Clinical Aspects and Novel Targeted Therapies

Cited by 8 publications

References 76 publications

An overview of chronic myeloid leukemia and its animal models

An overview of chronic myeloid leukemia and its animal models

Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia

Dup-697, a specific COX-2 inhibitor, suppresses growth and induces apoptosis on K562 leukemia cells by cell-cycle arrest and caspase-8 activation

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