Posted by rob on August 29, 2010 under Uncategorized | 
Destabilization of Bcr-Abl/Jak2 Network by a Jak2/Abl Kinase Inhibitor ON044580 Overcomes Drug Resistance in Blast Crisis Chronic Myelogenous Leukemia (CML).
Genes Cancer. 2010 May 19;1(4):346-359
Authors: Samanta AK, Chakraborty SN, Wang Y, Schlette E, Reddy EP, Arlinghaus RB
Bcr-Abl is the predominant therapeutic target in chronic myeloid leukemia (CML), and tyrosine kinase inhibitors (TKIs) that inhibit Bcr-Abl have been successful in treating CML. With progression of CML disease especially in blast crisis stage, cells from CML patients become resistant to imatinib mesylate (IM) and other TKIs, resulting in relapse. Because Bcr-Abl is known to drive multiple signaling pathways, the study of the regulation of stability of Bcr-Abl in IM-resistant CML cells is a critical issue as a possible therapeutic strategy. Here, we report that a new dual-kinase chemical inhibitor, ON044580, induced apoptosis of Bcr-Abl+ IM-sensitive, IM-resistant cells, including the gatekeeper Bcr-Abl mutant, T315I, and also cells from blast crisis patients. In addition, IM-resistant K562-R cells, cells from blast crisis CML patients, and all IM-resistant cell lines tested had reduced ability to form colonies in soft agar in the presence of 0.5 microM ON044580. In in vitro kinase assays, ON044580 inhibited the recombinant Jak2 and Abl kinase activities when the respective Jak2 and Abl peptides were used as substrates. Incubation of the Bcr-Abl+ cells with ON044580 rapidly reduced the levels of the Bcr-Abl protein and also reduced the expression of HSP90 and its client protein levels. Lysates of Bcr-Abl+ cell lines were found to contain a large signaling network complex composed of Bcr-Abl, Jak2, HSP90, and its client proteins as detected by a gel filtration column chromatography, which was rapidly disrupted by ON044580. Therefore, targeting Jak2 and Bcr-Abl kinases is an effective way to destabilize Bcr-Abl and its network complex, which leads to the onset of apoptosis in IM-sensitive and IM-resistant Bcr-Abl+ cells. This inhibitory strategy has potential to manage all types of drug-resistant CML cells, especially at the terminal blast crisis stage of CML, where TKIs are not clinically useful.
PMID: 20798787 [PubMed - as supplied by publisher]
More
Posted by rob on August 26, 2010 under Uncategorized |
A short cytochemical note on the nucleolar and cytoplasmic RNA concentration in differentiating cells represented by human erythroblasts.
Acta Histochem. 2010 Jul;112(4):407-11
Authors: Smetana K, Klamová H, Jirásková I, Mikulenková D
The present study was undertaken to provide more information on the nucleolar and cytoplasmic RNA concentration in differentiating cells of the erythroid lineage. These cells represent a convenient model to study cell differentiation since all stages are morphologically well characterised. The bone marrow of patients suffering from the chronic phase of chronic myeloid leukaemia without a large increase in the granulocyte to erythroid ratio provided erythroblasts for computer-assisted image density measurements of RNA in nucleoli and cytoplasm at the single cell level. The measurements indicated a significant decrease of the nucleolar and cytoplasmic RNA concentration only in advanced stages of erythroblast differentiation (polychromatic and orthochromatic erythroblasts). The ratio of the nucleolar to cytoplasmic RNA concentration was otherwise very stable and did not change during differentiation, being similar in the early and advanced stages of erythroblastic development. In contrast, the nucleolar size significantly decreased even during the early stages of erythroid development (basophilic erythroblasts). This marked decrease in the nucleolar diameter in differentiating erythroblasts and the less marked decrease in the nucleolar RNA concentration suggest that the amount of RNA in the nucleolus is closely associated with nucleolar size rather than on its concentration within the nucleolar body.
PMID: 19386355 [PubMed - indexed for MEDLINE]
More
Posted by rob on August 25, 2010 under Uncategorized |
Plasma adiponectin levels are markedly elevated in imatinib-treated chronic myeloid leukemia (CML) patients: a mechanism for improved insulin sensitivity in type 2 diabetic CML patients?
J Clin Endocrinol Metab. 2010 Aug;95(8):3763-7
Authors: Fitter S, Vandyke K, Schultz CG, White D, Hughes TP, Zannettino AC
CONTEXT: The mechanism(s) by which imatinib improves glycemic control in chronic myeloid leukemia (CML) patients with type 2 diabetes remains unclear. OBJECTIVE: Adiponectin is an important regulator of insulin sensitivity that is secreted exclusively by adipocytes. We previously reported that imatinib promotes adipocytic differentiation of mesenchymal stromal cells. We therefore hypothesized that imatinib therapy would be associated with an increase in peripheral and intramedullary adiposity and elevated plasma adiponectin levels. RESEARCH DESIGN AND METHODS: Adiponectin levels in CML patient plasma, at diagnosis and then during imatinib mesylate therapy, was measured using an ELISA. Adiponectin multimers in plasma were analyzed using nondenaturing PAGE and immunoblotting. Intramedullary adiposity and adipose tissue mass was determined using histomorphometry and dual-energy X-ray absorptiometry, respectively. RESULTS: In CML patients, an increase in intramedullary and peripheral adiposity was observed after 6 months of imatinib therapy and plasma adiponectin levels, in the form of high- and low-molecular-weight complexes, were elevated 3-fold, compared with pretreatment levels, after 3, 6, and 12 months of therapy. CONCLUSIONS: Elevated adiponectin levels in imatinib-treated CML patients provide a possible mechanism for improved glucose and lipid metabolism reported for some imatinib-treated patients.
PMID: 20466781 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
A T315I mutation in e19a2 BCR/ABL1 chronic myeloid leukemia responding to dasatinib.
Leuk Res. 2010 Sep;34(9):e240-2
Authors: Cea M, Cirmena G, Garuti A, Rocco I, Palermo C, Cagnetta A, Moran E, Colombo N, Grasso R, Fugazza G, Gobbi M, Nencioni A, Ballestrero A, Patrone F
PMID: 20447687 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Treating imatinib resistance in the few in CML-A key step towards cure in all.
Leuk Res. 2010 Sep;34(9):1123-4
Authors: Giles FJ
PMID: 20417556 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Changes in the use of hematopoietic stem cell transplantation: a model for diffusion of medical technology.
Haematologica. 2010 Apr;95(4):637-43
Authors: Gratwohl A, Schwendener A, Baldomero H, Gratwohl M, Apperley J, Niederwieser D, Frauendorfer K
BACKGROUND: Innovations in hematology spread rapidly. Factors affecting the speed of introduction, international diffusion, and durability of use of innovations are, however, poorly understood. DESIGN AND METHODS: We used data on 251,106 hematopoietic stem cell transplants from 591 teams in 36 European countries to analyze the increase and decrease in such transplants for breast cancer and chronic myeloid leukemia and the replacement of bone marrow by peripheral blood as the source of stem cells as processes of diffusion. Regression analyses were used to measure the quantitative impact of defined macro- and microeconomic factors, to look for significant associations (t-test), and to describe the coefficient of determination or explanatory content (R(2)). RESULTS: Gross national income per capita, World Bank category, team density, team distribution, team size, team experience and, team innovator status were all significantly associated with some or all of the changes. The analyses revealed different patterns of associations and a wide range of explanatory content. Macro- and micro-economic factors were sufficient to explain the increase of allogeneic hematopoietic stem cell transplants in general (R(2) = 78.41%) and for chronic myeloid leukemia in particular (R(2) = 79.39%). They were insufficient to explain the changes in stem cell source (R(2) =26.79% autologous hematopoietic stem cell transplants; R(2) = 9.67% allogeneic hematopoietic stem cell transplants) or the decreases in hematopoietic stem cell transplants (R(2) =10.22% breast cancer; R(2)=33.17% chronic myeloid leukemia). CONCLUSIONS: The diffusion of hematopoietic stem cell transplants is more complex than previously thought. Availability of resources, evidence, external regulations and, expectations were identified as key determinants. These data might serve as a model for diffusion of medical technology in general.
PMID: 20378578 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
A comment on Megakaryocytic blast crisis as a presenting manifestation of chronic myeloid leukemia.
Leuk Res. 2010 Sep;34(9):1253
Authors: Lazarevic VLj
PMID: 20378169 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Testicular cancer developed in a chronic myeloid leukemia patient with a continued complete cytogenetic and molecular response to imatinib. A case report and review of the literature.
Leuk Res. 2010 Sep;34(9):e229-31
Authors: Kata D, Mrówka-Kata K, Seweryn M, Pajak J, Najda J, Kyrcz-KrzemieÅ? S
PMID: 20359744 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Safety profiles of second-line tyrosine kinase inhibitors in patients with chronic myeloid leukaemia.
J Clin Nurs. 2010 May;19(9-10):1207-18
Authors: Tinsley SM
AIMS AND OBJECTIVES: To review the use of second-line tyrosine kinase inhibitors in patients with chronic myeloid leukaemia (CML) and provide recommendations for managing adverse events (AEs) to maximise patient benefit. BACKGROUND: Treatment of CML has been revolutionised with the advent of tyrosine kinase inhibitors (TKIs) that target the breakpoint cluster region-Abelson (BCR-ABL) kinase. Imatinib is the only first-line TKI currently available for the treatment of CML; however, intolerance and resistance remain significant clinical challenges. The approved second-line treatment options for CML are dasatinib, nilotinib or escalated-dose imatinib. DESIGN: Review article. METHODS: Searches of PubMed, ASCO and ASH electronic databases for relevant search terms were performed between July 2008-January 2009. FINDINGS: Dasatinib has no cross-intolerance with imatinib, and the most frequent AEs (cytopenias and pleural and pericardial effusions) can generally be managed by dose interruption and reduction. Nilotinib has a high degree of haematologic cross-intolerance with first-line imatinib. As might be expected, high-dose imatinib has the potential for more severe AEs than standard-dose imatinib. CONCLUSIONS: There are known safety issues inherent to each TKI and close monitoring by nursing staff is necessary to identify and effectively manage AEs. RELEVANCE TO CLINICAL PRACTICE: All three TKIs have demonstrated potential for fluid retention and cardiotoxicity. Nurses should be aware of how these AEs manifest and intervene appropriately. The safety profiles of these TKIs clearly differs and it is important to consider factors such as comorbidities when making treatment decisions.
PMID: 20345830 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Emerging drugs for chronic myeloid leukemia.
Expert Opin Emerg Drugs. 2010 Jun;15(2):175-84
Authors: Cilloni D, Messa E, Rotolo A, Saglio G
IMPORTANCE OF THE FIELD: The deregulated tyrosine kinase activity of BCR-ABL has been demonstrated to be necessary and sufficient to maintain leukemia phenotype of chronic myeloid leukemia (CML) which, therefore, represents a unique model for the development of molecular targeted therapy and the first disease in which the tyrosine kinase inhibitors (TKIs) completely changed the therapeutical approach. The impressive results of TKIs in this model have been overshadowed by the development of clinical resistance. AREAS COVERED IN THIS REVIEW: This review focuses on clinical results with imatinib therapy and second generation TKIs. Furthermore, a summary of the guidelines for the management of TKI resistant patients is provided together with a description of the new drugs in clinical or preclinical phases which are developing to overcome resistance. WHAT THE READER WILL GAIN: Future perspective for the ‘cure’ of CML patients and new drugs designed for this purpose are suggested. TAKE HOME MESSAGE: CML therapy has dramatically changed in the last few years due to the introduction of targeted therapy. Studies on new drugs targeting different pathways other than BCR-ABL are ongoing to improve the clinical results.
PMID: 20201747 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia.
Haematologica. 2010 Apr;95(4):582-8
Authors: Kim TD, Türkmen S, Schwarz M, Koca G, Nogai H, Bommer C, Dörken B, Daniel P, le Coutre P
BACKGROUND: Additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance. DESIGN AND METHODS: We assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations. RESULTS: Among 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients with-out additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations. CONCLUSIONS: Whereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy.
PMID: 20015884 [PubMed - indexed for MEDLINE]
More
Posted by rob on August 24, 2010 under Uncategorized |
Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia.
Blood. 2010 Aug 20;
Authors: Parkin B, Erba H, Ouillette P, Roulston D, Purkayastha A, Karp J, Talpaz M, Kujawski L, Shakhan S, Li C, Shedden K, Malek SN
Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML), and conventional karyotype-based risk classifications are routinely used in clinical decision making in AML. One of the known limitations of cytogenetic analysis is the inability to detect genomic abnormalities less than 5 Mb in size, and it is currently unclear whether overcoming this limitation with high-resolution genomic SNP array analysis would be clinically relevant. Furthermore, given the heterogeneity of molecular mechanisms/aberrations that underlie the conventional karyotype-based risk classifications, it is likely that further refinements in genomic risk prognostication can be achieved. Here, we have analyzed FACS-sorted AML blast-derived and paired buccal DNA from 114 previously untreated prospectively enrolled AML patients for acquired genomic copy number changes and LOH using Affymetrix SNP 6.0 arrays, and we have correlated genomic lesion load and specific chromosomal abnormalities with patient survival. Using multivariate analyses, we found that having >/=2 genomic lesions detected through SNP 6.0 array profiling approximately doubles the risk of death when controlling for age and karyotype-based risk. Finally, we have identified an independent negative prognostic impact of p53 mutations, or p53 mutations and 17p-LOH combined on survival in AML.
PMID: 20729466 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Hematological and toxicological evaluation of formaldehyde as a potential cause of human leukemia.
Hum Exp Toxicol. 2010 Aug 20;
Authors: Goldstein BD
Epidemiological findings suggesting that formaldehyde exposure is associated with a higher risk of acute myelogenous leukemia (AML) and other hematological cancers have led to consideration of the potential mechanism of action by which inhalation of this rapidly reactive agent can cause bone marrow cancer. Two major mechanism-based arguments against formaldehyde as a leukemogen have been the difficulty in envisioning how inhaled formaldehyde might penetrate to the bone marrow; and the lack of similarity of non-cancer effects to other known human myeloleukemogens, particularly the absence of pancytopenia in humans or laboratory animals exposed to high levels. However, both of these arguments have been addressed by the recent finding of a pancytopenic effect and chromosomal abnormalities in heavily exposed Chinese workers which, if replicated, are indicative of a genotoxic effect of formaldehyde on hematopoietic stem cells that is in keeping with other known human leukemogens. Review of the body of evidence suggests an apparent discrepancy between studies in laboratory animals, which generally fail to show evidence of penetration of formaldehyde into the blood or evidence of blood or bone marrow genotoxicity, and studies of exposed humans in which there tends to be evidence of genotoxicity in circulating blood cells. One possible explanation for this discrepancy is species difference. Another possible explanation is that myeloid precursors within the nasal mucosa may be the site for leukemogenesis. However, chloromas, which are local collections of myeloid tumor cells, are rarely if ever found in the nose. Other proposed mechanisms for formaldehyde leukemogenesis are reviewed, and dose issues at the interface between the epidemiological and hematotoxicological findings are explored.
PMID: 20729258 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin.
Bioorg Med Chem. 2010 Aug 1;
Authors: Yadav B, Taurin S, Rosengren RJ, Schumacher M, Diederich M, Somers-Edgar TJ, Larsen L
A series of 18 heterocyclic cyclohexanone analogues of curcumin have been synthesised and screened for their activity in both adherent and non-adherent cancer cell models. Cytotoxicity towards MBA-MB-231 breast cancer cells, as well as ability to inhibit NF-kappaB transactivation in non-adherent K562 leukemia cells were investigated. Three of these analogues 3,5-bis(pyridine-4-yl)-1-methylpiperidin-4-one B1, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one B10, and 8-methyl-2,4-bis((pyridine-4-yl)methylene)-8-aza-bicyclo[3.2.1]octan-3-one C1 showed potent cytotoxicity towards MBA-MB-231, MDA-MB-468, and SkBr3 cell lines with EC(50) values below 1muM and inhibition of NF-kappaB activation below 7.5muM. The lead drug candidate, B10, was also able to cause 43% of MDA-MB-231 cells to undergo apoptosis after 18h. This level of activity warrants further investigation for the treatment of ER-negative breast cancer and/or chronic myelogenous leukemia as prototypical cellular models for solid and liquid tumors.
PMID: 20728364 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Budgetary impact of treatment with adjuvant imatinib for 1 year following surgical resection of kit-positive localized gastrointestinal stromal tumors.
J Manag Care Pharm. 2010 Sep;16(7):482-91
Authors: Rubin JL, Taylor DC, Sanon M, Coombs JH, Bollu VK
BACKGROUND: Imatinib mesylate, an orally administered kinase inhibitor that targets the Kit (CD117) protein, currently has 10 approved indications including treatment of chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GIST). Treatment with adjuvant imatinib following surgical resection of localized Kit-positive GIST, the most recent FDA-approved indication (December 2008), has been shown to significantly improve recurrence-free survival (RFS) compared with surgical resection alone. Although adjuvant imatinib has proven effective in clinical trials, it is important to consider the economic impact to health plans of introducing imatinib in accordance with its new labeled indication. OBJECTIVE: To evaluate the budgetary impact over a 3-year time horizon of treating patients with localized Kit-positive GIST with 1 year of adjuvant imatinib following surgical resection. METHODS: A Markov model was developed to predict patients’ transitions across health states defined by initial treatment (surgical resection followed by adjuvant imatinib 400 milligrams [mg] daily versus surgical resection alone), recurrence, and progression. Treatments for a first recurrence were (a) imatinib 400 mg daily for recurrences following resection only or after completion of 1 year of treatment with imatinib 400 mg daily and (b) imatinib 800 mg daily for recurrence during active treatment with imatinib 400 mg daily. Treatments for further progression were imatinib 800 mg daily, sunitinib, or best supportive care (BSC) following imatinib 400 mg per day, and sunitinib or BSC following imatinib 800 mg daily. Recurrence rates were derived from the American College of Surgeons Oncology Group (ACOSOG) Z9001 clinical trial, which compared 1 year of adjuvant imatinib following surgical resection with surgical resection only. The total number of patients with localized and surgically resected GIST (incidence rate of 0.36 per 100,000) was estimated from epidemiologic studies of GIST. Uptake of treatment with imatinib was estimated from unpublished data from qualitative market research funded by the study sponsor. The uptake rate assumptions reflected both (a) the percentage of patients with Kitpositive disease and (b) the percentage of clinically eligible patients who would use imatinib. Costs were estimated by combining unit costs from published sources with expected resource utilization based on the clinical trial publication and National Comprehensive Cancer Network guidelines on the treatment of patients with GIST. To obtain estimates of the budgetary impact, we compared estimated health care costs with versus without adjuvant imatinib, where health care costs with imatinib reflected the costs of treatment minus cost offsets associated with delayed or avoided recurrence or progression. All “with” scenarios assumed no additional uses other than surgically resected localized Kit-positive GIST (i.e., no change in off-label use of imatinib). The budgetary impact was estimated for the first 3 years after the introduction of adjuvant imatinib in accordance with its new labeled indication in a hypothetical plan population of 10 million persons. Results were calculated both as total budgetary impact and as per member per month (PMPM) cost in 2009 dollars. Sensitivity analyses were performed to test the robustness of model results to changes in parameter estimates. RESULTS: The model predicted 36 incident resected GIST cases per year in a health plan of 10 million members. The estimated counts of cases treated with adjuvant imatinib were 10.8, 16.2, and 21.6 in the first, second, and third years after introduction, respectively, with the annual increases attributable to changes in the proportion of patients with resected GIST assumed to use imatinib (30% in year 1, rising to 45% in year 2 and 60% in year 3). The model predicted that treatment of these cases with imatinib will increase pharmacy costs by an additional $505,144 in the first year, $757,717 in the second year, and $1,010,289 in the third year. Increased resource use associated with monitoring patients during and after treatment with adjuvant imatinib would cost an additional $21,564, $38,145, and $56,605 in the first, second, and third years, respectively. Recurrence would be avoided or delayed in 7 patients over the 3-year period. Avoided or delayed recurrences would result in cost offsets of $61,583 in the first year, $156,702 in the second year, and $233,849 in the third year. The net budgetary impact was estimated to be $465,126 in the first year (less than $0.01 PMPM), $639,159 in the second year ($0.01 PMPM), and $833,044 in the third year ($0.01 PMPM). Results of sensitivity analyses indicated that the budgetary impact in the third year is most sensitive to changes in the price of adjuvant imatinib and recurrence rates. CONCLUSIONS: The model predicted that the introduction of adjuvant imatinib for treatment of surgically resected, localized, Kit-positive GIST will lead to a net budgetary impact of $0.01 PMPM in the third year after introduction assuming change in use only in accordance with the new labeled indication. Approximately 11.7%-21.9% of the cost of adjuvant imatinib is offset by the reduction in costs associated with GIST recurrence.
PMID: 20726677 [PubMed - in process]
More
Posted by rob on August 22, 2010 under Uncategorized |
[Expression of growth-factor independence 1 in patients with leukemia and its significance.]
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Jul;18(4):834-7
Authors: Wang TT, Chen ZX, Cen JN, He J, Sheng HJ, Yao L
This study was purposed to investigate the expression of the growth-factor independence 1 (GFI1) in patients with leukemia and its clinical significance. Bone marrow mononuclear cells were obtained from 65 newly diagnosed leukemia patients including 24 acute myeloid leukemia (AML), 18 chronic myelogenous leukemia (CML), 6 acute lymphoblastic leukemia (ALL), 17 blast crisis of chronic myelogenous leukemia and 13 patients with iron deficiency anemia (IDA) were used as controls. The relative expression of gene gfi1 was detected by reverse transcriptase-polyme-rase chain reaction (RT-PCR) and taqman quantitative real-time reverse transcription polymerase chain reaction (QRT-PCR). The results showed that gene expression of gene gfi1 in leukemia patients was obviously higher than that in controls and the difference was statistically significant (p < 0.01), in which the expression of gene gfi1 in newly diagnosed CML patients was higher than that in newly diagnosed AML, newly diagnosed ALL, CML-BCP patients and the difference was significant (p < 0.01). Expression of gene gfi1 in lymphocytic blast crisis of CML was higher than that in nonlymphocytic blast crisis of CML, and the difference was significant. It is concluded that gene gfi1 may play an important role in leukemia, especically in CML incidence and progression. The high level expression of gene gfi1 may be participate in the development of lymphoma.
PMID: 20723283 [PubMed - in process]
More
Posted by rob on under Uncategorized |
Establishment of the 1st World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA.
Blood. 2010 Aug 18;
Authors: White HE, Matejtschuk P, Rigsby P, Gabert J, Lin F, Wang YL, Branford S, Müller MC, Beaufils N, Beillard E, Colomer D, Dvorakova D, Ehrencrona H, Goh HG, El Housni H, Jones D, Kairisto V, Kamel-Reid S, Kim DW, Langabeer S, Ma ES, Press RD, Romeo G, Wang L, Zoi K, Hughes T, Saglio G, Hochhaus A, Goldman JM, Metcalfe P, Cross NC
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 PCR (RQ-PCR) methodologies that are employed 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. Following assessment of candidate cell lines, a reference material panel comprising four different dilution levels of freeze dried preparations of K562 cells diluted in HL60 cells was prepared. Following performance evaluation, the materials were assigned fixed % BCR-ABL/control gene values according to the International Scale. A recommendation that the four materials be established as the 1st World Health Organization (WHO) International Genetic Reference Panel for quantitation of BCR-ABL translocation by RQ-PCR was approved by the Expert Committee on Biological Standardization of the WHO in November 2009. We consider that the development of these reagents is a significant milestone in the standardization of this clinically important test, but since they are a limited resource we suggest that their availability is restricted to manufacturers of secondary reference materials.
PMID: 20720184 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
First-line therapy for chronic myeloid leukemia: new horizons and an update.
Clin Lymphoma Myeloma Leuk. 2010 Jun;10(3):169-76
Authors: Saglio G, Baccarani M
Although imatinib has shown unprecedented efficacy in the treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML), approximately one third of patients could benefit from a more effective treatment strategy. Several trials of next-generation agents and modified imatinib-based treatments are in progress, with the aim of improving on standard imatinib 400 mg per day therapy. In the post-imatinib era, a range of assessments are available for evaluating novel strategies. Based on existing evidence, achieving a complete cytogenetic response (CCyR) within 12 months provides the best prediction of longer-term benefit, although durable response and freedom from disease progression are the main treatment goals. In phase II studies, first-line treatment with dasatinib 100 mg once daily or nilotinib 400 mg twice daily resulted in high rates of CCyR and major molecular response (MMR) compared with historical data, and separate phase III trials are ongoing to compare each of these agents with imatinib for the treatment of newly diagnosed CP-CML. Preliminary results indicated higher 12-month CCyR and MMR and lower progression rates for nilotinib compared with standard-dose imatinib. Conflicting findings were reported regarding the ability of high-dose imatinib (800 mg per day) or imatinib plus interferon to induce higher response rates compared with standard-dose imatinib, although no improvement in progression-free survival or overall survival was reported. In the absence of trials comparing novel strategies, the synthesis of emerging data from next-generation agents and modified imatinib-based strategies is likely to be a key area of debate during the next few years.
PMID: 20511160 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Expression of oncogenic kinase Bcr-Abl impairs mitotic checkpoint and promotes aberrant divisions and resistance to microtubule-targeting agents.
Mol Cancer Ther. 2010 May;9(5):1328-38
Authors: Wolanin K, Magalska A, Kusio-Kobialka M, Podszywalow-Bartnicka P, Vejda S, McKenna SL, Mosieniak G, Sikora E, Piwocka K
Recent findings showed that BRCA1, in addition to its role in DNA damage response, acts as an upstream regulator of genes involved in the mitotic checkpoint regulation, thus protecting against promotion of aberrant divisions and aneuploidy. Moreover, there is also an indication that the BRCA1 protein is downregulated in chronic myeloid leukemia (CML) patients. We have investigated a possible functional relationship between BRCA1 and mitotic checkpoint competence in cells with the same genetic background expressing different levels of Bcr-Abl, an oncogene responsible for CML. Herein, we show that Bcr-Abl strongly downregulates the BRCA1 protein level, which is partially reversed on treatment with imatinib, an inhibitor of Bcr-Abl tyrosine kinase. Bcr-Abl leads to decreased expression of genes involved in the mitotic checkpoint activation–Mad2, Bub1, Bub3, and BubR1, resulting in mitosis perturbances, weakened mitotic checkpoint function, and mitotic slippage after nocodazole treatment. Furthermore, high Bcr-Abl-expressing cells showed also postmitotic checkpoint dysfunctions and inability to effectively arrest in the 4NG1 phase of the cell cycle, which was associated with limited p21 induction. These observations had significant biological consequences, as we found a high level of improper divisions, chromosomal missegregation, and generation of polyploid cells on mitotic checkpoint prolonged activation. Additionally, Bcr-Abl-expressing cells showed resistance to death activated by spindle defects, reversed by imatinib. Our study presents new facts and supports the hypothesis concerning the mutator nature of Bcr-Abl itself. The functional interaction between Bcr-Abl and mitosis dysfunctions, due to compromised mitotic checkpoints, may have important implications for the generation of aneuploidy and CML progression.
PMID: 20442314 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
The combination of thymosin and methylprednisolone for the treatment of a patient with colonic ulcers, subcutaneous nodules, and pleural effusion after dasatinib treatment for chronic myeloid leukemia.
Leuk Lymphoma. 2010 May;51(5):941-3
Authors: Chen J, Zheng Z, Shen J, Zhou Y
PMID: 20350280 [PubMed - indexed for MEDLINE]
More
