Posted by rob on June 24, 2010 under Uncategorized | 
Variant Isoforms of BCR-ABL1 in Chronic Myelogenous Leukemia Reflect Alternative Splicing of ABL1 in Normal Tissue – Letter.
Mol Cancer Ther. 2010 Jun 22;
Authors: Khorashad JS, Milojkovic D, Reid AG
Routine sequencing of the BCR-ABL kinase domain for the identification of resistance-associated point mutations is now a critical aspect of the management of chronic myeloid leukemia patients showing suboptimal response to imatinib. The recent correspondence between Lee and Santamaria (1-3) regarding the expression of an aberrant isoform of BCR-ABL1 in chronic myelogenous leukemia (CML) and the observation that the same insertion variant occurs in normal individuals (2) is therefore timely and relevant. In our experience and that of other groups, alternative splicing of BCR-ABL1 is not restricted to the BCR-ABL1(ins35) transcript reported by Lee et al. (1), but includes a variety of other isoforms (4, 5). The most common aberrant transcript we have observed harbored a deletion of exon 7 of ABL1 [ABL1(del7); identified in 82 of 236 (34%) CML patients]. Less common recurrent variations include complete or partial deletion of one or more ABL1 exons between 4 and 9, sometimes accompanied by partial insertion of intronic sequences. Although Lee and others have proposed a role for some of these splice variants in modulating BCR-ABL1 activity (1, 2), we found no correlation between the presence of a variant transcript and clinical features or likelihood of treatment response in patients with CML. Using the common exon 7 deletion as a model, we screened for the presence of similar alternative splicing of native ABL1 in normal individuals by reverse transcription-PCR and Scorpions-based allele-specific oligonucleotide PCR. Importantly, an ABL1(del7) transcript was detected in 4 of 17 normal cDNA samples. These observations argue against the notion that excision of exon 7 of ABL1 by alternative splicing is exclusively associated with CML and contradict the proposal of tyrosine kinase inhibitor therapy as a causative factor. Based on predictive analysis of protein structure, loss of exon 7 would confer no obvious novel function to the ABL1 molecule. Similarly, Sherbenou et al. (5) showed that BCR-ABL1 mutants lacking all or part of ABL1 exon 4 were catalytically inactive and did not interfere with the oncogenic activity of native BCR-ABL1. The expression of nonfunctional splice variants is not without precedent. Data generated by the ENCODE project indicate that many genes undergo a low level of alternative splicing, with little evidence to suggest that the alternative isoforms have a role as functional proteins (6). In the context of the clinical management of CML, it is therefore plausible that at least a proportion of the aberrantly spliced BCR-ABL1 transcripts are epiphenomena with no significant impact on disease course. The suggestions that expression of the BCR-ABL1(ins35) isoform increases relative to native BCR-ABL1 with prolonged exposure to imatinib and that the transcript is associated with resistance (1) are intriguing. However, such observations should be viewed with caution pending systematic validation using serial samples from imatinib-treated patients with a range of treatment responses and a sensitive means of quantifying relative expression of normal and aberrant transcripts. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
PMID: 20571070 [PubMed - as supplied by publisher]
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Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia.
Mol Cancer Res. 2010 Jun 22;
Authors: Kuroda J, Yamamoto M, Nagoshi H, Kobayashi T, Sasaki N, Shimura Y, Horiike S, Kimura S, Yamauchi A, Hirashima M, Taniwaki M
Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for beta-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC(50)s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl(T315I), or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines. Collectively, hGal9 is a candidate agent that may overcome various kinds of resistance to treatment for CML and may suggest that ATF3 may be a new target molecule for the development of new treatment modalities that can overcome resistance to currently available chemotherapeutics. Mol Cancer Res; 8(7); OF1-8. (c)2010 AACR.
PMID: 20571063 [PubMed - as supplied by publisher]
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The viscoelastic properties of microvilli are dependent upon the cell surface molecule.
Biochem Biophys Res Commun. 2010 Jun 3;
Authors: Python JL, Wilson KO, Snook JH, Guo B, Guilford WH
We studied at nanometer resolution the viscoelastic properties of microvilli and tethers pulled from myelogenous cells via P-selectin glycoprotein ligand 1 (PSGL-1) and found that in contrast to pure membrane tethers, the viscoelastic properties of microvillus deformations are dependent upon the cell-surface molecule through which load is applied. A laser trap and polymer bead coated with anti-PSGL-1 (KPL-1) were used to apply step loads to microvilli. The lengthening of the microvillus in response to the induced step loads was fitted with a viscoelastic model. The quasi-steady state force on the microvillus at any given length was approximately four-fold lower in cells treated with cytochalasin D or when pulled with concanavalin A-coated rather than KPL-1-coated beads. These data suggest that associations between PSGL-1 and the underlying actin cytoskeleton significantly affect the early stages of leukocyte deformation under flow.
PMID: 20570653 [PubMed - as supplied by publisher]
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P02-185 – Healthy siblings of children with cancer: the forgotten givers.
Eur Psychiatry. 2010;25S1:809
Authors: Karampela K, Hatira P, Damigos D
OBJECTIVES: To understand how healthy siblings visualize and represent health and disease as conditions affecting them and others in their family. Furthermore, to evaluate the emotional settings following health and disease for healthy siblings, the reasons lead to illness and what could be done to avoid that path. Additionally, this study aims to investigate the parameters that interfere with the physical and emotional living of healthy siblings and finally to access their subjective knowledge on disease and in particular, cancer. METHODS: Fourteen healthy children, aged between 7 and 14, siblings to children diagnosed and receiving treatment for leukemia (acute lymphoblastic & myelogenous leukemia), nephroblastoma (Wilms’ tumor), lymphoma, rhabdomyosarcoma, where evaluated according to the Hatira’s Projective Technique. RESULTS: Analyzing the interviews lead tomicron different kind of responses; some positive but mainly negative ones. The negative reactions addressed emotional instability, rejection, separation, siblings’ rivalry, the medical treatment itself and the fear of death, while positive reactions concerned self-awareness, sensitization, earlier maturing and increased family coherence after the crisis. CONCLUSION: The physical relationship between siblings is a special kind of human relationship that can outrun time and crises, even outgrowing in some cases the relationship between parents and their children. On the other hand, it is simultaneously a very fragile and vulnerable relationship, since traumatic experiences such as those arising from childhood cancer interfere with the mental and emotional growing of the healthy brother or sister, causing confusion to the body, mind and soul.
PMID: 20569906 [PubMed - as supplied by publisher]
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Two Novel Monoclonal Antibodies Against Human CD133-2: Distinct Epitopes and Agonist Activity to Enhance Growth of CD133 Expression Cells In Vitro.
Hybridoma (Larchmt). 2010 Jun;29(3):241-9
Authors: Wang J, Li F, Zhang G, Chen Y, Hu Y, Chen X, Lu B, Zhang X
Human AC133 antigen, also called CD133, is a unique transmembrane glycoprotein encoded by the PROM1 gene. It was initially suggested as a cell surface marker for hematopoietic stem/progenitor cells and has also been identified recently as a cancer stem cell marker in brain, colorectal, and prostate cancers. AC133 has two isoforms, one is AC133-1 and the other is AC133-2. Whether the two isoforms are functionally redundant or serve distinct functions remains unclear. In order to further explore the physiological and pathological functions of CD133-2, we generated two mouse antihuman CD133-2 monoclonal antibodies (clones 6B3 and 9G4). Then, we carefully characterized the biological functions of these monoclonal antibodies (MAbs) and showed that 6B3 and 9G4 bound to two epitopes of CD133, which are different from that recognized by the commercially available anti-CD133 MAb (AC141). These two MAbs could be used in cell immunostaining, Western blot, and immunohistochemical staining. We have further shown that MAb 6B3 enhances the growth of human myelogenous leukemic cell line U937 and human colon adenocarcinoma cell line SW480, suggesting a functional role of CD133 in these cells. Taken together as a useful tool, these two antibodies might be of great value for further exploration of the expression and function of CD133.
PMID: 20569000 [PubMed - in process]
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Posted by rob on June 21, 2010 under Uncategorized |
Acute Kidney Injury Presenting a Feature of Leukemic Infiltration during Therapy for Chronic Myelogenous Leukemia.
Intern Med. 2010;49(12):1139-42
Authors: Yuzawa Y, Sato W, Masuda T, Hamada Y, Tatematsu M, Yasuda Y, Ozaki T, Ito I, Mizuno M, Maruyama S, Ito Y, Matsuo S
Chronic myelogenous leukemia (CML) is a myeloproliferative disease that originates in abnormal pluripotent bone marrow stem cells and it is consistently associated with the Philadelphia chromosome and/or BCR/ ABL fusion gene. Renal infiltration of leukemic cells is relatively rare in CML and is associated with renal impairment. We describe a patient who developed acute renal failure by tubulointerstitial nephropathy during treatment with imatinib mesylate for CML. The acute kidney injury was subsequently found to be due to direct leukemic infiltration. Treatment with hydroxycarbamide and prednisolone resulted in stabilization of the renal function for approximately 4 months. Leukemic infiltration into the kidney should always be considered when a patient with CML presents with renal impairment, regardless of the clinical stage, as the renal failure often responds well to chemotherapy.
PMID: 20558931 [PubMed - in process]
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A single dose pegfilgrastim for supporting neutrophil recovery in patients treated for high-risk acute myeloid leukemia by the EMA 2000 schedule.
Hematology. 2010 Jun;15(3):125-31
Authors: Derbel O, Cannas G, Le QH, Elhamri M, Chelghoum Y, Nicolas-Virelizier E, Nicolini F, Troncy J, Barraco F, Michallet M, Thomas X
Dose intensity has been demonstrated to be one determinant for treatment efficacy in younger adults with high-risk (relapsed and refractory) acute myelogenous leukemia. Between 2000 and 2006, 56 patients entered the EMA 2000 study and received timed sequential reinduction chemotherapy. From 2004, chemotherapy was also followed by one subcutaneous dose of pegfilgrastim. Thirty-six patients reached a complete remission, while nine obtained a partial remission. Median time to granulocyte and platelet recovery was 34 and 38 days respectively. The major non-hematologic toxicities were severe infections but despite this 23 remitters could proceed to their post-remission treatment, although 13 did not because of severe toxicity or early relapse. The median overall survival was 9.3 months. The EMA 2000 regimen is a highly effective treatment with a response rate of 64% and a low early death rate. The period of critical neutropenia was relatively short in both phases and the supportive use of pegfilgrastim, although showing a trend toward reduced neutropenic period, did not appear to reduce the risk of infection in this group and may not be a critical requirement for reducing the risk of treatment-related toxicity.
PMID: 20557669 [PubMed - in process]
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Rapid clonal shifts in response to kinase inhibitor therapy in chronic myelogenous leukemia are identified by quantitation mutation assays.
Cancer Sci. 2010 May 22;
Authors: Yin CC, Cortes J, Galbincea J, Reddy N, Breeden M, Jabbour E, Luthra R, Jones D
Treatment of CML with the tyrosine kinase inhibitor (TKI) imatinib mesylate results in the emergence of point mutations within the kinase domain (KD) of the BCR-ABL1 fusion transcript. The introduction of next-generation TKIs that can overcome the effects of some BCR-ABL1 KD mutations requires quantitative mutation profiling methods to assess responses. We report the design and validation of such quantitative assays, using pyrosequencing and mutation-specific RT-PCR techniques, to allow sequential monitoring and illustrate their use in tracking specific KD mutations (e.g. G250E, T315I, and M351T) following changes in therapy. Pyrosequencing and mutation-specific RT-PCR allows sequential monitoring of specific mutations and identification of rapid clonal shifts in response to kinase inhibitor therapy in CML. Rapid reselection of TKI-resistant clones occurs following therapy switch in CML. (Cancer Sci 2010).
PMID: 20557306 [PubMed - as supplied by publisher]
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ABL alternative splicing is quite frequent in normal population – letter.
Mol Cancer Ther. 2010 Mar;9(3):772; author reply 772
Authors: Santamaria I, Pitiot AS, Balbin M
PMID: 20197392 [PubMed - indexed for MEDLINE]
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Content Type Journal ArticleCategory Letter to the EditorDOI 10.1007/s00277-010-1009-yAuthors
Ambra Spolverini, Università di Firenze, Istituto Toscano Tumori UF di Ematologia, Dipartimento di Area Critica Medico-Chirurgica Florence ItalyAmy V. Jones, University of Southampton Wessex Regional Genetics Laboratory, Salisbury, UK and Human Genetics Division, School of Medicine Southampton UKAndreas Hochhaus, Universitätsklinikum Jena Klinik für Innere Medizin II Jena GermanyLisa Pieri, Università di Firenze, Istituto Toscano Tumori UF di Ematologia, Dipartimento di Area Critica Medico-Chirurgica Florence ItalyNicholas C. P. Cross, University of Southampton Wessex Regional Genetics Laboratory, Salisbury, UK and Human Genetics Division, School of Medicine Southampton UKAlessandro M. Van…
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Content Type Journal ArticleCategory Letter to the EditorDOI 10.1007/s00277-010-1008-zAuthors
Shinichi Kobayashi, National Defense Medical College Division of Hematology, Department of Internal Medicine 3-2 Namiki Tokorozawa Saitama 359-8513 JapanKen Sato, National Defense Medical College Division of Hematology, Department of Internal Medicine 3-2 Namiki Tokorozawa Saitama 359-8513 JapanAyako Kobayashi, National Defense Medical College Division of Hematology, Department of Internal Medicine 3-2 Namiki Tokorozawa Saitama 359-8513 JapanYukiko Osawa, National Defense Medical College Division of Hematology, Department of Internal Medicine 3-2 Namiki Tokorozawa Saitama 359-8513 JapanYukitsugu Nakamura, National Defense Medical College Division of Hematology, Department of Internal Medicine …
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Posted by rob on June 18, 2010 under Uncategorized |
Imatinib-resistant lymphoid clone of chronic myelogenous leukemia in blast phase arising from B cell-committed progenitor leukemic stem cells.
Ann Hematol. 2010 Jun 17;
Authors: Kobayashi S, Sato K, Kobayashi A, Osawa Y, Nakamura Y, Kimura F
PMID: 20556391 [PubMed - as supplied by publisher]
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The myeloproliferative neoplasm-associated JAK2 46/1 haplotype is not overrepresented in chronic myelogenous leukemia.
Ann Hematol. 2010 Jun 16;
Authors: Spolverini A, Jones AV, Hochhaus A, Pieri L, Cross NC, Vannucchi AM
PMID: 20556390 [PubMed - as supplied by publisher]
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A case of acute colitis with severe rectal bleeding in a patient with chronic myeloid leukemia after dasatinib use.
Acta Haematol. 2010;123(4):205-6
Authors: Erkut M, Erkut N, Ersoz S, Arslan M, Sonmez M
PMID: 20375493 [PubMed - indexed for MEDLINE]
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Combination of fludarabine and imatinib induces apoptosis synergistically through loss of mitochondrial membrane potential and increases in caspase-3 enzyme activity in human K562 chronic myleloid leukemia cells.
Cancer Invest. 2010 Jul;28(6):623-8
Authors: Baran Y, Oztekin C, Bassoy EY
In this study, we aimed to show the synergistic apoptotic effects of imatinib/fludarabine combination in human K562 chronic myleloid leukemia (CML) cells. There was a significant increase in cytotoxicity of combination of imatinib and fludarabine as compared to any agent alone. On the other hand, combination of both agents induced apoptosis significantly as confirmed by increases in caspase-3 enzyme activity and decreases in mitochondrial membrane potential. As a summary, the results of this study strongly suggest that combination of imatinib and fludarabine induced cell death synergistically comparing to only imatinib or fludarabine in human K562 CML cells.
PMID: 20307198 [PubMed - indexed for MEDLINE]
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[Different sensitivity of two chronic myeloid leukemia cell lines to interferon-alpha]
Ai Zheng. 2003 Oct;22(10):1047-52
Authors: Li XM, Chen HC, Liu XF, Wu YH, Cao YF
BACKGROUND & OBJECTIVE: The clinical observation has shown that interferon-alpha(IFN-alpha) is one of the most effective therapeutic agents for the malignancies of hemopoietic system and lymphoma. However, IFN-alpha can only induce about 70-80% of the patients with chronic myeloid leukemia (CML) to get hematological remission. The mechanism by which various CML cases respond differently to IFN-alpha is still unclear. METHODS: (1)The effects of IFN-alpha in different concentrations (100, 500, 1,000, 5,000, and 10,000 U/ml) on growth of the two CML cell lines were detected by MTT assay,semisolid colony formation and trypan-blue staining for the cells in liquid culture. (2)The cell apoptosis was examined by flow cytometry(FCM),fluorescence microscopy and gel electrophoresis analysis for DNA fragmentation in 48 hours after IFN-alpha (1,000 U/ml) induction of both KT-1/A3 and K562 cells. (3)The expression levels of bcr/abl chimeric genes were analyzed by relative quantitative RT-PCR at 48 hours after cultivation of both KT-1/A3 and K562 cells with IFN-alpha in 1,000 U/ml. RESULTS: (1)The growth inhibition of KT-1/A3 cells was dose-dependent in IFN-alpha from the concentration of 100 U/ml to 10,000 U/ml. (2)Having been induced with IFN-alpha in 1000 U/ml for 48 hours, the apoptosis rate of KT-1/A3 cells raised from 3.29% to 11.8% and the expression level of bcr/abl chimeric gene in this cell line declined to 66.7% as compared with those of the control. (3)The growth and apoptosis rate as well as bcr/abl gene expression level of K562 cells were not significantly affected by IFN-alpha. CONCLUSION: Different populations of CML cells shows different sensitivity to IFN-alpha.
PMID: 14558948 [PubMed - indexed for MEDLINE]
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To the Editor: A 63-year-old white woman with a history of chronic myelogenous leukemia (CML) was referred to our clinic for evaluation of a 19-month history of worsening blistering and skin fragility of her extremities (). A previous biopsy specimen revealed a pauciinflammatory subepidermal split consistent with porphyria cutanea tarda (PCT) and negative direct immunofluorescence (DIF) with normal serum and urine porphyrin studies. Our biopsy of a characteristic lesion was consistent with PCT, with a negative DIF and repeat porphyrin studies that again were normal. Discontinuation of her thrice weekly naproxen and daily estrogen supplement for 12 weeks did not prevent skin blistering. Imatinib mesylate (IM; Gleevec; Novartis Pharmaceuticals, Cambridge, MA) had been used to treat her CML…
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We report the design and validation of such quantitative assays, using pyrosequencing and mutation-specific RT-PCR techniques, to allow sequential monitoring and illustrate their use in tracking specific KD mutations (e.g. G250E, T315I, and M351T) following changes in therapy. Pyrosequencing and mutation-specific RT-PCR allows sequential monitoring of specific mutations and identification of rapid clonal shifts in response to kinase inhibitor therapy in CML. Rapid reselection of TKI-resistant clones occurs following therapy switch in CML. (Cancer Sci 2010) (Source: Cancer Science)
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Posted by rob on June 13, 2010 under Uncategorized |
[Molecular targeting therapy for leukemia]
Gan To Kagaku Ryoho. 2010 May;37(5):806-10
Authors: Miyazaki Y
PMID: 20524248 [PubMed - indexed for MEDLINE]
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Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase.
Blood. 2010 May 20;115(20):4018-20
Authors: Pavlů J, Kew AK, Taylor-Roberts B, Auner HW, Marin D, Olavarria E, Kanfer EJ, MacDonald DH, Milojkovic D, Rahemtulla A, Rezvani K, Goldman JM, Apperley JF, Szydlo RM
Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second- and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib.
PMID: 20304808 [PubMed - indexed for MEDLINE]
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