Poppies
Posted by rob on June 19, 2006 under Uncategorized | 
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From Wilfried Joh
Bcr interacts with components of the endosomal sorting complex required for transport-I and is required for epidermal growth factor receptor turnover
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Olabisi OO, Mahon GM, Kostenko EV, Liu Z, Ozer HL, Whitehead IP.
Department of Microbiology and Molecular Genetics and University Hospital Cancer Center, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey.
Virtually all patients with chronic myelogenous leukemia (CML) express an aberrant protein (p210 Bcr-Abl) that contains NH(2)-terminal sequences from Bcr fused to COOH-terminal sequences from Abl. In a yeast two-hybrid screen, we have identified TSG101 as a binding partner for Bcr. Because TSG101 is a subunit of the mammalian endosomal sorting complex required for transport (ESCRT), which regulates protein sorting during endosomal trafficking, this association suggests that Bcr may have a related cellular function. The docking site for TSG101 has been mapped to the COOH terminus of Bcr, indicating that this interaction may be disrupted in CML. Overexpression studies with full-length TSG101 and Bcr reveal that this interaction can be recapitulated in mammalian cells. The association can also be observed between natively expressed proteins in a panel of hematopoietic and nonhematopoietic cell lines, where a second subunit of the ESCRT complex, vacuolar sorting protein 28 (Vps28), was also found to interact with Bcr. Both Bcr and TSG101 exhibit a punctate cytoplasmic distribution and seem to colocalize in HeLa cells, which would be consistent with an in vivo association. Bacterially purified Bcr and TSG101 also bind, suggesting that the interaction is direct and is not dependent on ubiquitination. Disruption of the endosomal pathway with an ATPase-defective Vps4 mutant results in the cellular redistribution of Bcr, and suppression of Bcr in HeLa cells by small interfering RNA impairs epidermal growth factor receptor turnover. Taken together, these observations suggest that Bcr is a component of the mammalian ESCRT complexes and plays an important role in cellular trafficking of growth factor receptors. (Cancer Res 2006; 66(12): 6250-7).
PMID: 16778200 [PubMed - in process]
Panniculitis during dasatinib therapy for imatinib-resistant chronic myelogenous leukemia.
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Assouline S, Laneuville P, Gambacorti-Passerini C.
Publication Types:
PMID: 16775249 [PubMed - in process]
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.
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Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG.
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA. hkantarj@mdanderson.org
BACKGROUND: Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50. METHODS: In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily. RESULTS: Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission. CONCLUSIONS: Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML. (ClinicalTrials.gov number, NCT00109707 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
PMID: 16775235 [PubMed - in process]
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.
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Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL.
Department of Leukemia, M.D. Anderson Cancer Center, Houston, USA.
BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
PMID: 16775234 [PubMed - in process]
Philadelphia chromosome of a constitutional der(22)t(Y;22)(q11.2;p11) with a variant t(1;9;22)(p36;q34;q11) in a case of chronic myelogenous leukemia.
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Buijs A, Terhal PA, Thunnissen PL.
Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center, Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands.
Publication Types:
PMID: 16772126 [PubMed - in process]
JWA as a Novel Molecule Involved in Oxidative Stress-Associated Signal Pathway in Myelogenous Leukemia Cells
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Zhu T, Chen R, Li A, Liu J, Gu D, Liu Q, C Chang H, Zhou J.
Department of Molecular Cell Biology and Toxicology, Jiangsu Provincial Key Laboratories of Human Functional Genomics and of Applied Toxicology, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China.
Previous data showed that JWA might be a novel environmental responsive gene regulated by environmental stressors such as heat shock and oxidative stress. However, the molecular mechanism underlying JWA gene function involved in oxidative stress is still unknown. In this study, the potential role of JWA was further investigated in hydrogen peroxide (H2O2) induced DNA damage and cell apoptosis in K562 cells. Series of the oxidative stress models were established to observe if JWA was involved in DNA damage or cell apoptosis induced by H2O2 exposure. These results indicated that the inhibitory effect on K562 cells’ viability induced by H2O2 was concentration and time dependent. JWA was more sensitive to H2O2 (0.01 mmol/L) than the heat-shock proteins (hsp70 and hsp27), and its expression pattern was similar to that of hsp70. In addition, JWA, hsp70, hsp27, and p53 were overexpressed and the expression patterns of JWA, hsp70, and p53 were similar during cell apoptosis. H2O2 led to the cleavage and activation of procaspase-3. In conclusion, these results suggested that JWA might be an effective environmental responsive gene that functions as a parallel with hsp70 in oxidative stress-responsive pathways in K562 cells. Like hsp70, JWA might enhance intracellular defenses and function against H2O2-induced oxidative stress in leukemia cells. At the same time, JWA was involved in the p53-associated signal pathways of oxidative stress-induced apoptosis, which is also caspase-3 dependent.
PMID: 16766476 [PubMed - as supplied by publisher]
[False-positive hepatitis serology after administration of immunoglobulins.]
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[Article in German]
Institut fur Medizinische Mikrobiologie, Immunologie und Krankenhaushygiene.
HISTORY: A 17-year-old boy with chronic myelogenous leukemia received a bone marrow transplantation (BMT) from an unrelated donor. 22 days before BMT he had been HBs antigen and anti-HBc negative. 68 days after BMT he was tested again and showed a “seroconversion” for hepatitis B (anti-HBc positive, anti-HBs 59 IU/l), raising the suspicion of a posttransfusion hepatitis. The patient had not received any blood transfusion in the 6 months before BMT. From day 0 to day + 68 he received four red blood cell concentrates and 18 platelet concentrates. The bone marrow donor had been HBs ag and anti-HBc negative. INVESTIGATIONS: A stored serum sample of the recipient obtained on day -8 was available and proved to be negative for HBsAg and Anti-HBc IgM, but positive for anti-HBc and anti-HBs. A serum sample from day -22 was negative for all these parameters. DIAGNOSIS: These results can be explained by the administration of 17.5 g of a polyvalent immunoglobulin (Ig) concentrate for CMV prophylaxis on day -9: anti-HBc and anti-HBs (1814 IU/l) were found in the lot that the patient had received. Nine further doses of immunoglobulin concentrates were given up to day + 68. COURSE: Four months after the last administration of Ig concentrates, the patient was negative for HBs ag, anti-HBc and anti-HBs. CONCLUSION: Ig concentrates contain not only those antibodies, which are given to a patient for treatment, but also all other antibodies contained in the donor plasma pool. Thus administration of Ig concentrates can cause a “false-positive” hepatitis B serology by passive transfer of these antibodies. Such an artificial seroconversion may also lead to a false suspicion of a transfusion transmitted hepatitis B infection.
PMID: 16761202 [PubMed - in process]
Effects of C/EBPalpha and C/EBPbeta in BCR/ABL-Expressing Cells: Differences and Similarities.
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Guerzoni C, Ferrari-Amorotti G, Bardini M, Mariani SA, Calabretta B.
Department of Biomedical Sciences, Universita di Modena e Reggio Emilia, Modena, Italy.
C/EBPalpha and C/EBPbeta, two transcription factors of the C/EBP family play important roles in the proliferation and differentiation of various cell types including myeloid progenitors. Expression of C/EBPalpha and C/EBPbeta is repressed in myeloid blast crisis of Chronic Myelogenous Leukemia by mechanisms that involve translation repression which depends on the interaction of RNA-binding proteins with conserved binding sites in the 5′UTR of c/ebpalpha and c/ebpbeta mRNA. Ectopic expression of C/EBPalpha and C/EBPbeta in myeloid progenitors expressing the BCR/ABL oncogene inhibits proliferation, induces differentiation and suppresses leukemogenesis in mice, but C/EBPalpha is markedly more effective than C/EBPbeta. The more potent effects of C/EBPalpha probably depends on protein-protein interaction with cell-cycle regulatory proteins, but the pattern of genes modulated by C/EBPalpha and C/EBPbeta is not completely overlapping. This suggests that transcription-dependent and -independent effects are both involved and support the therapeutic potential of reactivating C/EBPalpha and C/EBPbeta expression in leukemic cells.
PMID: 16760662 [PubMed - as supplied by publisher]
Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance.
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Azam M, Nardi V, Shakespeare WC, Metcalf CA 3rd, Bohacek RS, Wang Y, Sundaramoorthi R, Sliz P, Veach DR, Bornmann WG, Clarkson B, Dalgarno DC, Sawyer TK, Daley GQ.
*Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Division of Hematology/Oncology, The Children’s Hospital, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA 02115.
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM(R)) BCR/ABL kinase variants. Both compounds potently inhibit most IM(R) variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM(R)-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.
PMID: 16754879 [PubMed - in process]
Preclinical assessment of FHIT gene replacement therapy in human leukemia using a chimeric adenovirus, Ad5/F35.
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Pichiorri F, Trapasso F, Palumbo T, Aqeilan RI, Drusco A, Blaser BW, Iliopoulos D, Caligiuri MA, Huebner K, Croce CM.
Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA. pichiorri.1@osu.edu
PURPOSE: Expression of the FHIT protein is lost or reduced in most solid tumors and a significant fraction of hematopoietic malignancies. Adenovirus 5 (Ad5) virus or adeno-associated viral vectors have been used to study the tumor suppressor function of FHIT in solid tumors, but these tools have not been effective in leukemias. We have generated a chimeric FHIT-containing adenovirus composed of Ad5 and the group B adenovirus called F35 with which we have been able to efficiently infect hematopoietic cells. EXPERIMENTAL DESIGN: Infection efficiency of Ad5/F35-FHIT and Ad5/F35-GFP viruses was tested in leukemia cell lines that lacked FHIT expression, and biological effects of successful infection were assessed. An acute myelogenous leukemia, a chronic myelogenous leukemia, and four acute lymphoblastic leukemia human cell lines were examined as well as two EBV-transformed B lymphoblastoid cell lines that expressed endogenous FHIT. RESULTS: Two of four acute lymphoblastic leukemia cell lines, Jurkat and MV4;11, which were efficiently infected with Ad5/F35-FHIT, underwent growth suppression and massive induction of apoptosis without apparent activation of caspase-8 or caspase-2 and late activation of caspase-3. Treatment of infected cells with caspase-9 and caspase-3 inhibitors partially blocked FHIT-induced apoptosis. The two remaining infected acute lymphoblastic leukemia cell lines, Molt-3 and RS4;11, were apparently unaffected. Restoration of FHIT expression in the chronic myelogenous leukemia K562 cell line and the acute myelogenous leukemia KG1a cell line also induced apoptosis but at later time points than seen in the acute lymphoblastic leukemia Jurkat and MV4;11 cell lines. I.v. injection of Ad5/F35-FHIT-infected Jurkat cells resulted in abrogation of tumorigenicity in the NOD/SCID xenogeneic engraftment model. CONCLUSION: FHIT restoration in some FHIT-deficient leukemia cells induces both antiproliferative and proapoptotic effects involving the intrinsic caspase apoptotic pathway.
PMID: 16740775 [PubMed - in process]
New Leukemia Drugs
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Five years ago, the drug Gleevec changed the lives of patients with leukemia. But some patients become resistant to Gleevec over time. Now, doctors are studying two new treatments that are even more potent.
This is more than a visit to a botanical garden for Amy Baker. It’s part of what she calls her “leukemic” adventure. Baker was diagnosed with chronic myelogenous leukemia or CML. She first took the drug Gleevec (imatinib).
“[Gleevec] is a pill you take once a day and actually produces complete remission of this disease,” says Kapil Bhalla, M.D., a hematologist/oncologist at Moffitt Cancer Center and Research Institute in Tampa, Fla.
But Baker became resistant to Gleevec. Her only option was a clinical trial in Florida. Baker lives in Ohio, so every 28 days, she hops a plane. “I made up my mind when I was going to do this I would call this my leukemic adventure,” she says.
In his clinical trial, Dr. Bhalla is studying two drugs that are more potent than Gleevec, AMN107 and dasatinib. He says they are making a big difference in the progression of the disease in patients who have developed resistance to Gleevec.
With this type of leukemia, parts of chromosomes 9 and 22 switch places, creating abnormality called the Philadelphia Chromosome. Knowing this, Dr. Bhalla tells Ivanhoe, “We have a target in this disease.”
When it comes to AMN107, Baker has rave reviews. “You don’t lose your hair,” she says. “You don’t get really, really sick.” And it’s working. Before the treatment, her Philadelphia Chromosome level was at 90 percent, and now it’s down to 2.5 percent — a big improvement. Today, she’s happily enjoying life and looking forward to fulfilling many other adventures.
Some patients with CML who can get to remission are then able to get a bone marrow transplant, which can be a cure for this disease. Dr. Bhalla says these new drugs have made this option available to more and more patients with CML who have a bone marrow match.
If you would like more information, please contact:
Linda Loudon
Moffitt Cancer Center
Cancer Answers, FOW/LCS
12902 Magnolia Dr.
Tampa, FL 33612
(800) 456-7121