Posted by rob on January 20, 2012 under Uncategorized | 
[Mechanism of cinnamic aldehyde-inducing apoptosis of chronic myeloid leukemic cells in vitro].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Jun;19(3):617-20
Authors: Liu LQ, Liu ZL, Wang X, Cui HY, Jin MD, Wang DY, Huang SA
Abstract
The aim of this study was to investigate the apoptosis-inducing effect of cinnamic aldehyde (CA) on chronic myeloid leukemic (CML) cells and its mechanism. K562 cells and primary bone marrow mononuclear cells (MNC) from patients with CML were treated by various concentrations of CA. Flow cytometry was employed to measure the apoptosis of K562 cells and primary CML bone marrow MNC. Western blot was used to determine the expression of C-MYC and the phosphorylation of CrkL in K562 cells, and real-time polymerase chain reaction (real-time PCR) was used to quantify the expression of BCR-ABL mRNA in K562 cells. The results indicated that CA induced the apoptosis of K562 cells in a time- and dose-dependent manner. CA induced apoptosis of CML MNC dose-dependently. CA inhibited the expression of BCR-ABL mRNA and C-MYC, reduced CrkL phosphorylation levels in K562 cells. It is concluded that CA induces apoptosis of CML cells in vitro. Down-regulation of the expression and function of BCR-ABL may be one of its most important anti-leukemia mechanisms.
PMID: 21729535 [PubMed - indexed for MEDLINE]
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[Expression of CIAPIN1 gene in BMMNC of patients with leukemia].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Jun;19(3):570-3
Authors: Li B, Li QH, Lin YN, Jin WN, Pang TX
Abstract
This study was aimed to investigate the expression level of CIAPIN1 mRNA in leukemia patients and explore its significance in leukemias. The fresh bone marrow was collected from 112 newly diagnosed leukemia patients, the total RNA was extracted by means of TRIzoL, the cDNA was synthesized, the expression of CIAPIN1 mRNA was detected by real-time quantitative PCR using ?-actin as internal reference; 10 normal healthy persons were selected as controls. The results showed that the expression of CIAPIN1 mRNA was statistically higher in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and chronic phase chronic myeloid leukemia (CML) patients than that in normal persons (p < 0.05); but there was no statistical difference between chronic lymphocytic leukemia (CLL) and normal persons (p > 0.05). It is concluded that the CIAPIN1 gene higher expresses in MNC of newly diagnosed leukemia patients, up-regulation of CIAPIN1 expression may play an important role in pathogenesis of leukemia.
PMID: 21729524 [PubMed - indexed for MEDLINE]
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Posted by rob on January 19, 2012 under Uncategorized |
We report that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter-driven, self-renewing, leukemia-initiating cells to result in B-lymphoid leukemia (B-ALL) in vivo. In vitro, highly proliferating and serially replatable myeloid and lymphoid colony-forming cultures could be established from BCR-ABL and Bmi1 coexpressing progenitors. However, unlike in vivo expanded CML B-lymphoid progenitors, hematopoietic stem cells, or multipotent progenitors, coexpressing BCR-ABL and Bmi1 did not initiate or propagate leukemia in a limiting dilution assay. Inducible genetic attenuation of BCR-ABL reversed Bmi1-driven B-ALL development, which was accompanied by induction of apoptosis of leukemic B-lymphoid progenitors and by long-term animal survival, suggesti…
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Chronic myelogenous leukemia (CML) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein. Clinically, CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis. A CML-specific immune response is thought to contribute to the control of disease. Whether the immune system can also promote disease progression is not known. In the present study, we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells (LSCs) and mediates effects of the immune system on CML. In a mouse model of CML, BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27. Binding of CD27 by its ligand, CD70, increased expression of Wnt target …
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Conclusions.-In gastrointestinal stromal tumors, the strongest predictor of response to targeted therapies is the mutational status of KIT or PDGFRA. Patients whose tumors harbor a KIT exon 11 mutation benefit the most from imatinib mesylate therapy, in terms of response rate, progression-free survival, and overall survival. Conversely, tumors without detectable mutations in either gene (“wild-type” gastrointestinal stromal tumors) are generally not responsive to imatinib mesylate.
PMID: 22229850 [PubMed - as supplied by publisher] (Source: Archives of Pathology and Laboratory Medicine)
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Modeling of Molecular Interaction between Apoptin, BCR-Abl and CrkL – An Alternative Approach to Conventional Rational Drug Design.
PLoS One. 2012;7(1):e28395
Authors: Panigrahi S, Stetefeld J, Jangamreddy JR, Mandal S, Mandal SK, Los M
Abstract
In this study we have calculated a 3D structure of apoptin and through modeling and docking approaches, we show its interaction with Bcr-Abl oncoprotein and its downstream signaling components, following which we confirm some of the newly-found interactions by biochemical methods. Bcr-Abl oncoprotein is aberrantly expressed in chronic myelogenous leukaemia (CML). It has several distinct functional domains in addition to the Abl kinase domain. The SH3 and SH2 domains cooperatively play important roles in autoinhibiting its kinase activity. Adapter molecules such as Grb2 and CrkL interact with proline-rich region and activate multiple Bcr-Abl downstream signaling pathways that contribute to growth and survival. Therefore, the oncogenic effect of Bcr-Abl could be inhibited by the interaction of small molecules with these domains. Apoptin is a viral protein with well-documented cancer-selective cytotoxicity. Apoptin attributes such as SH2-like sequence similarity with CrkL SH2 domain, unique SH3 domain binding sequence, presence of proline-rich segments, and its nuclear affinity render the molecule capable of interaction with Bcr-Abl. Despite almost two decades of research, the mode of apoptin’s action remains elusive because 3D structure of apoptin is unavailable. We performed in silico three-dimensional modeling of apoptin, molecular docking experiments between apoptin model and the known structure of Bcr-Abl, and the 3D structures of SH2 domains of CrkL and Bcr-Abl. We also biochemically validated some of the interactions that were first predicted in silico. This structure-property relationship of apoptin may help in unlocking its cancer-selective toxic properties. Moreover, such models will guide us in developing of a new class of potent apoptin-like molecules with greater selectivity and potency.
PMID: 22253690 [PubMed - in process]
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Ponatinib: Targeting the T315I Mutation in Chronic Myelogenous Leukemia.
Clin Adv Hematol Oncol. 2011 Dec;9(12):925-6
Authors: Shah NP
PMID: 22252660 [PubMed - in process]
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Estimation of current cumulative incidence of leukaemia-free patients and current leukaemia-free survival in chronic myeloid leukaemia in the era of modern pharmacotherapy.
BMC Med Res Methodol. 2011;11:140
Authors: Pavlík T, Janoušová E, Pospíšil Z, Mužík J, Zá?ková D, Rá?il Z, Klamová H, Cetkovský P, Trn?ný M, Mayer J, Dušek L
Abstract
BACKGROUND: The current situation in the treatment of chronic myeloid leukaemia (CML) presents a new challenge for attempts to measure the therapeutic results, as the CML patients can experience multiple leukaemia-free periods during the course of their treatment. Traditional measures of treatment efficacy such as leukaemia-free survival and cumulative incidence are unable to cope with multiple events in time, e.g. disease remissions or progressions, and as such are inappropriate for the efficacy assessment of the recent CML treatment.
METHODS: Standard nonparametric statistical methods are used for estimating two principal characteristics of the current CML treatment: the probability of being alive and leukaemia-free in time after CML therapy initiation, denoted as the current cumulative incidence of leukaemia-free patients; and the probability that a patient is alive and in any leukaemia-free period in time after achieving the first leukaemia-free period on the CML treatment, denoted as the current leukaemia-free survival. The validity of the proposed methods is further documented in the data of the Czech CML patients consecutively recorded between July 2003 and July 2009 as well as in simulated data.
RESULTS: The results have shown a difference between the estimates of the current cumulative incidence function and the common cumulative incidence of leukaemia-free patients, as well as between the estimates of the current leukaemia-free survival and the common leukaemia-free survival. Regarding the currently available follow-up period, both differences have reached the maximum (12.8% and 20.8%, respectively) at 3 years after the start of follow-up, i.e. after the CML therapy initiation in the former case and after the first achievement of the disease remission in the latter.
CONCLUSIONS: Two quantities for the evaluation of the efficacy of current CML therapy that may be estimated with standard nonparametric methods have been proposed in this paper. Both quantities reliably illustrate a patient’s disease status in time because they account for the proportion of patients in the second and subsequent disease remissions. Moreover, the model is also applicable in the future, regardless of what the progress in the CML treatment will be and how many treatment options will be available, respectively.
PMID: 21988861 [PubMed - indexed for MEDLINE]
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Posted by rob on January 9, 2012 under Uncategorized |
A compound produced from fish oil that appears to target leukemia stem cells could lead to a cure for the disease, according to Penn State researchers. The compound — delta-12-protaglandin J3, or D12-PGJ3 — targeted and killed the stem cells of chronic myelogenous leukemia, or CML, in mice, said Sandeep Prabhu, associate professor of immunology and molecular toxicology in the Department of Veterinary and Medical Sciences. The compound is produced from EPA — Eicosapentaenoic Acid — an Omega-3 fatty acid found in fish and in fish oil, he said… (Source: Health News from Medical News Today)
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Conclusions.-Validation of laboratory-developed quantitative molecular tests requires careful planning and execution to adequately address all required analytic performance parameters. How these are addressed depends on the potential for technical errors and confidence required for a given test result. We demonstrate how one laboratory validated and clinically implemented a quantitative BCR-ABL1 assay that can be used for the management of patients with chronic myelogenous leukemia.
PMID: 22208485 [PubMed - in process] (Source: Archives of Pathology and Laboratory Medicine)
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Authors: Bates SE, Amiri-Kordestani L, Giaccone G
Abstract
A British humorist said, “There is much to be said for failure. It is much more interesting than success.” This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a num…
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Abstract Chronic myelogenous leukemia (CML) is a common myeloproliferative disease that is characterized by the clonal expansion of
marrow stem cells, and is associated with the Philadelphia chromosome. As the disease progresses, additional chromosome abnormalities may arise. The prognostic impact of secondary
chromosomal abnormalities in CML is complex, heterogeneous, and sometimes related to previous treatment. Here, we describe
a CML patient in lymphoid blast crisis associated with a new chromosomal abnormality identified, dic(7;12)(p12.21;p12.2) and
i(12)(q10) using classical cytogenetics and spectral karyotype analysis. To the best of our knowledge, this is the first report
of t(7;12)(p11.1;q11.1) and i(12)(q10) in a CML patient with lymphoid evolution.
Content Ty…
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Authors: Holstein SA, Hohl RJ
Abstract
Approval of agents for the treatment of cancers by the US Food and Drug Administration (FDA) was granted to only six new chemical entities in the three years spanning 2008 to 2010. By contrast, in the first nine months of 2011, six new chemical entities were approved for use in cancer. This approval rate is unprecedented and reflects the advances in science since the approval of the first monoclonal antibody (rituximab) in 1997 and the first targeted small-molecule tyrosine kinase inhibitor (imatinib) in 2001 for non-Hodgkin’s lymphoma and chronic myelogenous leukemia, respectively. Here we briefly discuss the newly approved agents, a possible deletion from the therapeutic armamentarium, and the use of the FDA accelerated approval process.
…
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Targeting cancer stem cells is of paramount importance in successfully preventing cancer relapse. Recently, in silico screening of public gene-expression datasets identified cyclooxygenase-derived cyclopentenone prostaglandins (CyPGs) as likely agents to target malignant stem cells. We show here that 12-PGJ3, a novel and naturally produced CyPG from the dietary fish-oil -3 polyunsaturated fatty acid eicosapentaenoic acid (EPA; 20:5) alleviates the development of leukemia in 2 well-studied murine models of leukemia. IP administration of 12-PGJ3 to mice infected with Friend erythroleukemia virus or those expressing the chronic myelogenous leukemia oncoprotein BCR-ABL in the hematopoietic stem cell pool completely restored normal hematologic parameters, splenic histology, and enhanced surviva…
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Abstract The BCR/ABL-negative myeloproliferative neoplasms (MPNs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis,
over the natural course of their disease, have an increasing predisposition to transform to overt acute myeloid leukemia (AML)—most
appropriately referred to as MPN-blast phase (MPN-BP). Although this transformation is a rare event, once AML has occurred,
it is associated with a poor response to therapy and short survival. The molecular events leading to transformation are poorly
defined. Currently, no therapy other than allogeneic stem cell transplantation (ASCT) has been demonstrated to alter the natural
history of this disease. Multiple therapeutic investigations are currently ongoing, including early ASCT, hypomethylating
agent…
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Cancer researchers studying genetic mutations that cause leukemia have discovered a connection to the rare disease cherubism, an inherited facial bone disorder in children. The link is the enzyme Tankyrase and its pivotal role in switching on or off the protein that controls two known cancer genes. In normal cells, the protein is vital for bone development. In abnormal cells, it is thought to be involved in two common types of blood cancer – chronic myelogenous leukemia and acute myeloid leukemia. The findings, published online today in CELL (DOI: 10.1016/j.cell.2011.10… (Source: Health News from Medical News Today)
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Abstract Imatinib is a powerful protein tyrosine kinase (PTK) inhibitor that specifically targets BCR-ABL, KIT, and PDGFR kinases,
has become the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Beside PTKs, PTK inhibitors
alter the activity of a large number of voltage-dependent ion channels. hERG1 K+ channels are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis. The present
study explored a possible regulatory effect of imatinib upon hERG1 K+ channels as a means to uncover new molecular events involved in the antileukemic activity of this PTK inhibitor in CML. The
results demonstrated that hERG1 was highly detected in K562 cells and primary CML cells, and down-regulated by imatinib at
mRNA…
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CONCLUSIONS:BCR?ABL1 expression up?regulated HO?1, a survival factor for CML cells. This up?regulation was more pronounced in blast crisis CML relative to early stage disease and was mediated by the NADPH oxidase components Rac1 and p47phox. The expression of p47phox was increased in BCR?ABL1–expressing cells. Cancer 2011. © 2011 American Cancer Society. (Source: Cancer)
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Conclusions Our data suggest the potential usefulness of DOK2 as a marker of poor prognosis in patients with gastric cancer after curative
resection.
Content Type Journal ArticleCategory Gastrointestinal OncologyPages 1-8DOI 10.1245/s10434-011-2157-6Authors
Hiromichi Miyagaki, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanMakoto Yamasaki, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanTsuyoshi Takahashi, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanYukinori Kurokawa, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanHiroshi Miyata, Department of Gastroent…
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In this study, we found that treatment with ABL kinase inhibitors or depletion of BCR-ABL induced the expression of RAB45 messenger RNA and protein and induced apoptosis via reduction of mitochondrial membrane potential and p38 activation in CML cell lines and BCR-ABL+ progenitor cells from CML patients. Overexpressed RAB45 induced the activation of caspases-3 and -9 and reduced the expression of Survivin, XIAP, c-IAP1 and c-IAP2 in CML cells. Moreover, in colony-forming cells derived from CML-aldehyde dehydrogenasehi/CD34+ cells, treatment with ABL kinase inhibitors induced RAB45 expression and reduced mitochondrial membrane potential, resulting in inhibited colony formation of Bcr-Abl+ progenitor cells. The overexpression of RAB45 significantly decreased colony numbers and induced apopto…
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