Posted by rob on February 5, 2011 under Uncategorized | 
Arsenic, a curative agent for acute promyelocytic leukemia, induces cell apoptosis and degradation of BCR-ABL in chronic myelogenous leukemia (CML). We demonstrated that ubiquitination and degradation of BCR-ABL was mediated by c-CBL, a RING-type E3 ligase that was also shown to be involved in ubiquitination for many other receptor/protein tyrosine kinases. Our data showed that c-CBL protein was considerably up-regulated by arsenic sulfide (As4S4). Interestingly, arsenic directly bound the RING finger domain of c-CBL to inhibit its self-ubiquitination/degradation without interfering with the enhancement of ubiquitination and subsequent proteolysis of its substrate BCR-ABL. Degradation of BCR-ABL due to c-CBL induction as a result of arsenic treatment was also observed in vivo in CML mice. …
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Bristol-Myers Squibb today announced that SPRYCEL(R) (dasatinib) 100mg once daily received Marketing Authorization from the European Commission for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukaemia in Chronic Phase (CML-CP). Sprycel is the first new approved treatment in the E.U. with superior efficacy vs. imatinib in this indication since 2001… (Source: Health News from Medical News Today)
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AbstractSrc family kinases (SFKs) are frequently over?expressed and/or activated in human cancers, and play key roles in cancer cell invasion, metastasis, proliferation, survival, and angiogenesis. Allosteric activation of SFKs occurs through well?defined post?translational mechanisms, however the SFK member Fyn is over?expressed in multiple human cancers (prostate, melanoma, pancreatic, glioma, chronic myelogenous leukemia) and the mechanism of increased Fyn expression is unclear. Since activation of Ras oncogenes is a common oncogenic event leading to the activation of multiple effector pathways, we explored if Ras could induce Fyn expression. Retroviral transduction of the human keratinocyte cell line HaCaT with oncogenic H?Ras dramatically up?regulated Fyn mRNA (>100?f…
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Authors: Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D
Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of chronic myelogenous leukemia. The effect of coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib was evaluated in an open-label, randomized, 2-period, crossover study. Healthy subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with multiple once-daily doses of oral ketoconazole 400 mg. PK sampling occurred through 96 hours. The least square geometric mean treatment ratios (90% confidence interval [CI]) of C(max(bosutinib+ketoconazole))/C(max(bosutinib alone)), AUC(T(bosutinib+ketoconazole))/AUC(T(bosutinib alone)), and AUC((bosutinib+ketoconazole))/AUC((bosutinib a…
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In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)–resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels o…
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Summary Myeloproliferative neoplasms (MPN) are clonal haemopoietic progenitor cell disorders characterized by the proliferation of
one or more of the haemopoietic lineages (myeloid, erythroid and/or megakaryocytic). The MPNs include eight haematological
disorders: chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis
(PMF), systemic mastocytosis (SM), chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), chronic neutrophilic
leukemia (CNL), and unclassifiable MPN (MPN, U). Therapeutic interventions for MPNs include the use of tyrosine kinase inhibitors
(TKIs) for BCR-ABL1+ CML and JAK2 inhibitors for PV, ET and PMF. Histone deacetylase inhibitors (HDACi) are a novel class of drugs capable of
altering …
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Abstract: A 9?year?old female spayed mixed breed dog was evaluated at the University of Florida Small Animal Hospital for marked leukocytosis with no associated clinical signs. CBC abnormalities included marked leukocytosis (106,000/?L), marked monocytosis (78,000/?L), and the presence of 13% blast cells (13,832/?L), supporting a diagnosis of leukemia. Cytopenias and dysplastic changes in other cell lines were not present. Microscopic examination of bone marrow showed hypercellular uniparticles with a marginal increase in frequency of unclassified blast cells (2%), but was otherwise unremarkable. Flow cytometric immunophenotyping of blood cells determined that leukemic cells were CD45+, CD14+, and CD34–, and based on side scatter and CD45 reactivity the marrow contained 19% monobl…
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We report a case of blastic crisis of CML with both t(3;3)(q21;q26.2) and t(9;22)(q34;q11.2) and associated severe multilineage dysplasia. The patient showed a poor response to imatinib, dasatinib and aggressive induction therapy. When both t(3;3)(q21;q26.2) and t(9;22)(q34;q11.2) are observed in cases of leukemia with increased blasts, they are best considered as aggressive phases of CML with t(3;3)(q21;q26.2), rather than AML with t(9;22)(q34;q11.2) by 2008 WHO classification.
PMID: 21157145 [PubMed - as supplied by publisher] (Source: The Korean Journal of Laboratory Medicine)
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Abstract: Carbohydrate N-acetylgalactosamine 4-0 sulfotransferase 9 (CHST9) belongs to the N-acetylgalactosamine 4-sulfotransferase (GalNAc4ST) family. A recent array-based study implicated the presence of copy-number variations (CNV) of the region encompassing CHST9 in the genomes of acute myelogenous leukemia. Most of the current studies, however, focused on the genome-wide screening of CNV, and the functional impact of such regions needs to be extensively investigated in large amounts of clinical samples. In our study, we collected 617 bone marrow samples from multi-types of hematologic malignancies, as well as healthy controls, and detected the CNV of CHST9 by real-time polymerase chain reaction (PCR). We found significant association between the CNV of CHST9 and these hematologic mali…
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In the article “Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenic and prognostic implications” by Zaccaria et al. on behalf of the GIMEMA Working Party on CML the group claim that the Ph occurred “secondary or biclonally with other chromosomal abnormalities (ACA) in some Ph positive patients with CML treated by imatinib (group 1). Their conclusions are based only on the cytogenetic evidence. There is a large body of published evidence utilizing simultaneously many clonal markers (such as X-linked G6PD, HUMARA, cytogenetics IGH, etc.) since 1977 with subsequent confirmed publications clearly demonstrating that rmultistep pathogenesis of CML is initiated in the multipotent CD34+ cells with clonal origin being…
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I thank Prof. Najfeld for her comments. Her letter allows me to clarify some points. I do not disagree about the multistep process of CML and the possibility that the Philadelphia chromosome (Ph) or other additional chromosome abnormalities (ACAs) occur in an already clonal CD34+ multipotent stem cell. This is not the point. What we tried to say in our paper was that, according to cytogenetic studies, the persistence of ACA after imatinib treatment, which hits only BCR/ABL1 carrying cells, would indicate that ACA occurred before the Ph, and that this clone was previously undetected due to the proliferative advantage of the Ph positive one. Briefly, a small, slowly proliferating, ACA+ clone acquires the t(9;22). The new, active proliferating ACA+, Ph+ clone suppresses the original clone whi…
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I am very grateful to Dr. Zaccaria’s clarification. However, the main point remains. To suggest that CML has a biclonal origin, based on cytogenetic evidence alone is a misleading perception since there are plenty of literature documented that the Philadelphia chromosome (Ph) and an additional chromosomal abnormalities (ACA), such as +8, originate from a primordial CD34+ cell that is clonal. Therefore, primordial CD34+ clonal cells are genetically unstable and develop various cytogenetic abnormalities and those with the proliferative advantage such as the Ph, or +8 are cytogenetically detected. As mentioned in the original communication , cytogenetics alone does not have a power to answer the question whether Ph or ACA occurred first. Designing a study to answer these questions may be ve…
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In conclusion, Rakicidin A is a promising compound for targeting TKI?resistant quiescent CML stem cells in the hypoxic BM environment. (Source: Cancer Science)
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Serial quantitation of BCR-ABL mRNA levels is an important indicator of therapeutic response for patients with chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia, but there is substantial variation in the real-time quantitative polymerase chain reaction methodologies used by different testing laboratories. To help improve the comparability of results between centers we sought to develop accredited reference reagents that are directly linked to the BCR-ABL international scale. After assessment of candidate cell lines, a reference material panel comprising 4 different dilution levels of freeze-dried preparations of K562 cells diluted in HL60 cells was prepared. After performance evaluation, the materials were assigned fixed percent BCR-ABL/co…
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Abstract Imatinib mesylate has become a therapy of interest for the treatment of systemic sclerosis because of its ability to inhibit
c-Abl and platelet-derived growth factor receptor, tyrosine kinases involved in profibrotic pathways. Preclinical data using
in vitro and murine models of fibrosis have demonstrated the antifibrotic properties of imatinib. Imatinib is currently used
widely in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other conditions, and a large
amount of information is available regarding the safety of the medication in these patient populations. Whether imatinib will
be tolerable or effective in the treatment of systemic sclerosis is the subject of several investigations. The aim of this
review is to summarize thi…
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Conclusions Histopathologic analysis is not useful as a routine diagnostic tool in EM because no morphological changes are specific to EM. The capillary proliferation and vasculopathy are assumed to be a consequence of intermittent skin hypoxia (vascular hypothesis of pathogenesis). Whether the proliferation is a consequence of EM or a pathogenic factor in the development of the disease is uncertain. (Source: Archives of Dermatology)
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Abstract: Imatinib mesylate is currently the standard therapy for chronic myelogenous leukemia patients. Despite the remarkable results achieved with imatinib, the emergence of resistance to this drug has become a significant problem. Actually, two other second-generation tyrosine kinase inhibitors have been used for resistant/intolerant patients to imatinib. With the availability of oral tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia, questions relating to adherence to prescribed therapy have become an important issue. It has been demonstrated that the effectiveness of the treatment with imatinib requires high compliance to the prescribed dose of the drug for an indefinite period of time, whereas reduced adherence to therapy has been associated with delay in …
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In this study, we queried whether miR-107 and paralogs regulated GRN in human cancers. In cultured cells, anti-argonaute RNA coimmunoprecipitation with downstream microarray analyses indicates that GRN mRNA is directly targeted by numerous miR-15/107 miRNAs. We further tested this association in human tumors. MiR-15 and miR-16 are known to be downregulated in chronic lymphocytic leukemia (CLL). Using pre-existing microarray datasets, we found that GRN expression is higher in CLL relative to nonneoplastic lymphocytes (P < 0.00001). By contrast, other prospective miR-15/miR-16 targets in the dataset (BCL-2 and cyclin D1) were not upregulated in CLL. Unlike in CLL, GRN was not upregulated in chronic myelogenous leukemia (CML) where miR-107 paralogs are not known to be dysregulated. Prior s…
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Inhibition of Grb2 expression demonstrates an important role in BCR–ABL-mediated MAPK activation and transformation of primary human hematopoietic cells
Leukemia advance online publication, November 12, 2010. doi:10.1038/leu.2010.257
Authors: H Modi, L Li, S Chu, J Rossi, J-K Yee
& R Bhatia (Source: Leukemia)
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Paraneoplastic phenomena have previously been reported in patients with chronic myelogenous leukemia (CML). A number of papers describe CML patients with paraneoplastic skin lesions identified during or after the diagnosis of CML. Among those, solitary or multiple papules, plaques and nodules have been described . These lesions are most commonly identified on legs and arms, followed by back, anterior chest, face and scalp . Generalized maculopapular eruptions have also been reported in patients with CML. (Source: Leukemia Research)
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