Posted by rob on December 22, 2005 under Uncategorized | 
Park J, Kim S, Oh JK, Kim JY, Yoon SS, Lee D, Kim Y
J Biochem Mol Biol. 2005 Nov 30; 38(6): 725-38
Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a 1 microM imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.
Identification of differentially expressed proteins in imatinib mesylate-resistant chronic myelogenous cells.
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Fugazza G, Garuti A, Marchelli S, Miglino M, Bruzzone R, Gatti AM, Castello S, Sessarego M
Cancer Genet Cytogenet. 2005 Dec ; 163(2): 173-5
The cytogenetic studies and molecular evaluation of a Philadelphia chromosome negative chronic myelogenous leukemia patient with trisomy 21 (100% metaphases) and trisomy 9 (50% metaphases) at diagnosis are described. Fluorescence in situ hybridization revealed an atypical location of the BCR/ABL fusion signal on 9q, which was duplicated in cells with trisomy 9 simulating a double Ph. The patient was successfully treated with Glivec (also known as Gleevec; Novartis, Basel, Switzerland) and achieved complete hematological and cytogenetic response as well as a reduction of BCR/ABL transcripts detected by real-time quantitative PCR.
Masked Philadelphia chromosome due to atypical BCR/ABL localization on the 9q34 band and duplication of the der(9) in a case of chronic myelogenous leukemia.
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Millot F, Guilhot J, Nelken B, Leblanc T, De Bont ES, B?kassy AN, Gadner H, Sufliarska S, Stary J, Gschaidmeier H, Guilhot F, Suttorp M
Leukemia. 2005 Dec 8;
A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon alpha-based regimen. In all, 30 children from eight European countries were enrolled. In 18 children assessable for hematologic response, imatinib mesylate induced complete hematologic response in eight (80%) of the 10 patients included in chronic phase and in six (75%) of eight enrolled in advanced phase of the disease with acceptable toxicity. In 27 patients assessable for cytogenetic response, imatinib mesylate induced disappearance of Philadelphia chromosome-positive bone marrow cells in 12 (60%) of 20 children included in chronic phase and in two (29%) of seven included in advanced phase. A reduction of the bcr-abl/abl ratio to less than 10(-4) was achieved in 11 (50%) of the children included in chronic phase. Estimated 12-month overall survival rate was 95% (95% CI, 87-100%) for the patients included in chronic phase and 75% (95%CI, 45-100%) for those enrolled in advanced phase. Imatinib mesylate is well tolerated and molecular remission can be achieved in children with CML.Leukemia advance online publication, 8 December 2005; doi:10.1038/sj.leu.2404051.
Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation.
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Borthakur G, Kantarjian H, Daley G, Talpaz M, O’brien S, Garcia-Manero G, Giles F, Faderl S, Sugrue M, Cortes J
Cancer. 2005 Dec 8;
BACKGROUND: Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models. METHODS: In the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib. Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily. Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib. The median age of the patients was 62 years (range, 38-80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3-13 yrs). In addition to imatinib mesylate, all patients had received prior therapy with interferon-alpha and seven patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2-41 wks). RESULTS: Two patients responded. One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months. Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months. The most common adverse event was diarrhea, which was noted in 11 patients (84%) (Grade >/= 3 in 4 patients; 31%; toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments. CONCLUSIONS: Single-agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib. Cancer 2006. (c) 2005 American Cancer Society.
Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy.
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Bornh?user M, Kr?ger N, Schwerdtfeger R, Schafer-Eckart K, Sayer HG, Scheid C, Stelljes M, Kienast J, Mundhenk P, Fruehauf S, Kiehl MG, Wandt H, Theuser C, Ehninger G, Zander AR,
Eur J Haematol. 2006 Jan ; 76(1): 9-17
Objective: To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome-positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM). Methods: We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling (n = 18) or unrelated (n = 43) donors after having been treated with IM. Forty-one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan (n = 25) or total-body irradiation (n = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose-reduced conditioning with fludarabine-based regimens. Results: The incidence of grades II-IV and III-IV graft-versus-host disease was 66% and 38% respectively. The probability of overall survival (OS), disease-free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non-relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine-based conditioning therapy, age >/=40 yr and >12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM. Conclusion: These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant-related mortality.
Allogeneic haematopoietic cell transplantation for chronic myelogenous leukaemia in the era of imatinib: a retrospective multicentre study.
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J Zhejiang Univ Sci B. 2005 Dec; 6(12): 1141-7
Sun J, Huang H, Zhu YY, Lan JP, Li JY, Lai XY, Yu J
OBJECTIVE: Detecting the expression and mutation of human telomeric repeat binding factor (hTRF1) in 10 malignant hematopoietic cell line cells on the base of determining its genomic structure and its four pseudogenes to clarify if hTRF1 mutation is one of the factors of the activation of telomerase. METHODS: hTRF1cDNA sequences were obtained from GenBank, its genome structure and pseudogenes were forecasted by BLAST and other biology information programs and then testified by sequencing. Real-time RT-PCR was used to detect the expression of hTRF1mRNA in 10 cell line cells, including myelogenous leukemia cell lines K562, HL-60, U-937, NB4, THP-1, HEL and Dami; lymphoblastic leukemia cell lines 6T-CEM, Jurkat and Raji. Telomerase activities of cells were detected by using telomeric repeat amplification (TRAP)-ELISA protocol. PCR and sequencing were used to detect mutation of each exon of hTRF1 in 10 cell line cells. RESULTS: hTRF1 gene, mapped to 8q13, was divided into 10 exons and spans 38.6 kb. Four processed pseudogenes of hTRF1 located on chromosome 13, 18, 21 and X respectively, was named as PsihTRF1-13, PsihTRF1-18, PsihTRF1-21 and PsihTRF1-X respectively. All cell line cells showed positive telomerase activity. The expression of hTRF1 was significantly lower in malignant hematopoietic cell lines cells (0.0338, 0.0108-0.0749) than in normal mononuclear cells (0.0493, 0.0369-0.128) (P=0.004). But no significant mutation was found in all exons of hTRF1 in 10 cell line cells. Four variants were found in part of intron 1, 2 and 8 of hTRF1. Their infection on gene function is unknown and needs further studies. CONCLUSION: hTRF1 mutation is probably not one of the main factors for telomerase activation in malignant hematopoietic disease.
Study on the expression and mutation of human telomeric repeat binding factor (hTRF1) in 10 malignant hematopoietic cell lines.
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Ma X, Ruan G, Wang Y, Li Q, Zhu P, Qin YZ, Li JL, Liu YR, Ma D, Zhao H
Clin Cancer Res. 2005 Dec 15; 11(24): 8592-9
PURPOSE: Chronic myelogenous leukemia (CML) is a disease characterized cytogenetically by the presence of the Philadelphia chromosome. Recent studies suggested that altered PDCD5 expression may have significant implications in CML progression. The aim of this study was to identify single-nucleotide polymorphisms (SNP) within the programmed cell death 5 (PDCD5) promoter region and show their functional relevance to PDCD5 expression as well as their genetic susceptibility to CML.EXPERIMENTAL DESIGN: One hundred twenty-nine CML subjects and 211 healthy controls were recruited for identification of SNPs and subsequent genetic analysis. Luciferase reporter assays were carried out to show the functional significance of the SNPs located in the promoter region to PDCD5 expression. Real-time quantitative PCR and Western blot analysis were done to determine the expression differences of PDCD5 in CML patients with different genotypes.RESULTS: Two SNPs were identified within the PDCD5 promoter. They are -27A>G and -11G>A (transcription start site as position 1), respectively. The complete linkage disequilibrium was found between these two polymorphisms. The frequencies of -27G(+)/-11A(+) genotype and -27G/-11A allele were significantly higher in CML patients than in healthy controls (genotype: 26.36% versus 11.85%, chi(2)=11.75, P HubMed Abstracts
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Rezvani K, Brenchley JM, Price DA, Kilical Y, Gostick E, Sewell AK, Li J, Mielke S, Douek DC, Barrett AJ
Clin Cancer Res. 2005 Dec 15; 11(24): 8799-8807
PURPOSE: Antigens derived from the Wilms’ tumor (WT1) protein, which is overexpressed in leukemias, are attractive targets for immunotherapy. Four HLA-A*0201-restricted WT1-derived epitopes have been identified: WT37, WT126, WT187, and WT235. We determined the natural immunogenecity of these antigens in patients with hematologic malignancies and healthy donor.EXPERIMENTAL DESIGN: To detect very low frequencies of WT1-specific CD8(+) T cells, we used quantitative reverse transcription-PCR to measure IFN-gamma mRNA production by WT1 peptide-pulsed CD8(+) T cells from 12 healthy donors, 8 patients with chronic myelogenous leukemia, 6 patients with acute myelogenous leukemia, and 8 patients with acute lymphoblastic leukemia.RESULTS: Responses were detected in 5 of 8 chronic myelogenous leukemia patients, 4 of 6 patients with acute myelogenous leukemia, and 7 of 12 healthy donors. No responses were detected in patients with acute lymphoblastic leukemia. The magnitude and extent of these CD8(+) T-cell responses was greater in patients with myeloid leukemias than in healthy donors. Clonotypic analysis of WT1-specific CD8(+) T cells directly ex vivo in one case showed that this naturally occurring population was oligoclonal. Using fluorescent peptide-MHC class I tetramers incorporating mutations in the alpha3 domain (D227K/T228A) that abrogate binding to the CD8 coreceptor, we were able to confirm the presence of high-avidity T-cell clones within the antigen-specific repertoire.CONCLUSION: The natural occurrence of high-avidity WT1-specific CD8(+) T cells in the periphery could facilitate vaccination strategies to expand immune responses against myeloid leukemias.
HubMed Abstracts
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Haltrich I, Kost-Alimova M, Kov?cs G, Kriv?n G, Tam?ska J, Klein G, Fekete G, Imreh S
Cancer Genet Cytogenet. 2006 Jan 1; 164(1): 74-80
The virtually obligatory presence of the Philadelphia chromosome may suggest a causal homogeneity, but chronic myelogenous leukemia (CML) is a clinically heterogeneous disease. This may be a consequence of the variable BCR breakpoints on chromosome 22 and of nonrandom secondary chromosomal abnormalities. We present the case of a boy, age 12, investigated in blastic phase of CML. Karyotyping with conventional and multiplex fluorescence in situ hybridization (FISH and M-FISH) karyotyping, complemented with reverse transcriptase-polymerase chain reaction, identified a variant Philadelphia translocation t(9;14;22)(q34;q32;q11) involving a cryptic BCR/ABL fusion with formation of the p190(Bcr-Abl) oncoprotein. M-FISH revealed also an unbalanced jumping translocation of 17q11 approximately qter alternatively present on chromosomes 14 or 20, apparently hithertofore unreported in hematological malignancies. Another secondary aberration, dup(3)(q25q28), was revealed by multipoint interphase FISH (mpI-FISH). Gain of this region is known in adult hematological malignancies and solid tumors, suggesting its general involvement in tumor initiation or progression (or both), regardless of tissue origin.
Jumping translocation of 17q11 approximately qter and 3q25 approximately q28 duplication in a variant Philadelphia t(9;14;22)(q34;q32;q11) in a childhood chronic myelogenous leukemia.
