Posted by rob on January 28, 2010 under Uncategorized | 
Resveratrol Promotes Autophagic Cell Death in Chronic Myelogenous Leukemia Cells via JNK-Mediated p62/SQSTM1 Expression and AMPK Activation.
Cancer Res. 2010 Jan 26;
Authors: Puissant A, Robert G, Fenouille N, Luciano F, Cassuto JP, Raynaud S, Auberger P
Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy. Cancer Res; 70(3); 1042-52.
PMID: 20103647 [PubMed - as supplied by publisher]
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Efficacious Immune Therapy in Chronic Myelogenous Leukemia (CML) Recognizes Antigens That Are Expressed on CML Progenitor Cells.
Cancer Res. 2010 Jan 26;
Authors: Biernacki MA, Marina O, Zhang W, Liu F, Bruns I, Cai A, Neuberg D, Canning CM, Alyea EP, Soiffer RJ, Brusic V, Ritz J, Wu CJ
Curative effects of graft-versus-leukemia-based therapies such as donor lymphocyte infusion (DLI) for chronic myelogenous leukemia (CML) may result from immunologic ablation of self-renewing CML progenitor cells. Patients who achieved durable remissions after DLI developed a significant B-cell lymphocytosis after treatment, which did not occur in patients who were unresponsive to DLI. In this study, we identified antigen targets of this B-cell response by probing two immunoproteomic platforms with plasma immunoglobulins from seven CML patients with clinically apparent graft-versus-leukemia responses after DLI. In total, 62 antigens elicited greater reactivity from post-DLI versus pre-DLI plasma. Microarray analysis revealed that >70% of the antigens were expressed in CML CD34(+) cells, suggesting that expression in malignant progenitor cells is a feature common to antibody targets of DLI. We confirmed elevated expression of three target antigens (RAB38, TBCE, and DUSP12) in CML that together consistently elicited antibody responses in 18 of 21 of an additional cohort of CML patients with therapeutic responses, but not in normal donors and rarely in non-CML patients. In summary, immunologic targets of curative DLI responses include multiple antigens on CML progenitor cells, identifying them as potential immunogens for vaccination and/or monitoring of immunotherapeutics designed to eliminate myeloid leukemia stem cells. Cancer Res; 70(3); 906-15.
PMID: 20103624 [PubMed - as supplied by publisher]
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Therapy of B-cell malignancies by anti-HLA-DR humanized monoclonal antibody, IMMU-114, is mediated through hyper-activation of ERK and JNK MAP kinase signaling pathways.
Blood. 2010 Jan 25;
Authors: Stein R, Gupta P, Chen X, Cardillo TM, Furman RR, Chen S, Chang CH, Goldenberg DM
The expression of HLA-DR on hematological malignancies has stimulated interest in its development as a target for antibody-based therapy. A humanized IgG4 anti-HLA-DR mAb (IMMU-114), engineered to avoid side effects associated with complement-activation, was examined for binding and cytotoxicity on leukemia, lymphoma, and multiple myeloma cell lines (MM) and chronic lymphocytic leukemia (CLL) patient specimens, followed by evaluation of the effects of IMMU-114 on ERK and JNK signaling pathways. HLA-DR was expressed on the vast majority of these cells at markedly higher levels than CD20, CD22, and CD74. IMMU-114 was toxic to mantle cell lymphoma, CLL, acute lymphoblastic leukemia, hairy cell leukemia, non-Hodgkin lymphoma (including rituximab-resistant), and MM cell lines, and also patient CLL cells. IMMU-114 induced disease-free survival in tumor-bearing SCID mice with early-stage disease and in models that are relatively resistant to anti-CD20 mAbs. Despite positive staining, acute myelogenous leukemia cells were not killed by IMMU-114. The ability of IMMU-114 to induce activation of ERK and JNK signaling correlated with cytotoxicity and differentiates the mechanism of action of IMMU-114 from mAbs against CD20 and CD74. Thus, antigen expression is not sufficient for cytotoxicity; antibody-induced hyper-activation of ERK and JNK MAP kinase signaling pathways also are required.
PMID: 20101022 [PubMed - as supplied by publisher]
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Ecthyma gangrenosum caused by Escherichia coli bacteremia: a case report and review of the literature.
Cutis. 2009 Nov;84(5):261-7
Authors: Patel JK, Perez OA, Viera MH, Halem M, Berman B
Ecthyma gangrenosum (EG) is a serious and well-recognized cutaneous condition. Development of EG is most commonly associated with Pseudomonas aeruginosa septicemia. Other organisms, such as Escherichia coli, have been identified less often as the cause of EG. We describe a 50-year-old man previously diagnosed with acute myelogenous leukemia (AML) who developed an E coli-colonized EG lesion secondary to E coli bacteremia. This case represents the seventh of its kind in the literature and the first case in a patient with AML. In addition, a brief review of the etiopathology and management of EG is presented.
PMID: 20099619 [PubMed - in process]
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The chemokine system and its contribution to leukemogenesis and treatment responsiveness in patients with acute myeloid leukemia.
J BUON. 2009 Sep;14 Suppl 1:S131-40
Authors: Olsnes AM, Hatfield KJ, Bruserud Ø
The chemokine family consists of approximately 50 small (8-14 kDa), basic proteins that are expressed and released by a wide range of normal and malignant cells. Most chemokines act through heptahelical transmembrane G protein- coupled receptors. Based on their molecular structure these cytokines are divided into the two major subgroups CCL and CXCL chemokines that bind to CCR or CXCR receptors respectively. Primary human acute myelogenous leukemia (AML) cells show constitutive release of a wide range of chemokines, but the chemokine release profile differs between patients. Among the commonly expressed chemokines are proangiogenic CXCL8, antiangiogenic CXCL4/9-11 and several leukocyte-chemotactic chemokines. Systemic serum levels of leukocyte-chemotactic chemokines depend both on patient age, disease status, the chemotherapy regimen and development of complicating infections. The local chemokine network in human AML is probably further modulated by the hypoxic bone marrow microenvironment and the local release of chemokines by nonleukemic bone marrow stromal cells. Usually primary AML cells also express several chemokine receptors. Specific chemokine inhibitors are now being developed, including chemokine-neutralizing or receptor-blocking antibodies, antisense strategies, receptor-blocking small molecules or inhibitors of downstream signaling. The use of CXCR4-antagonists for mobilization of peripheral blood stem cells has been documented in several clinical studies. Although animal studies suggest that chemokine inhibition also may become useful in the treatment of graft versus host disease, the possible use of chemokine-targeting therapy for other indications than stem cell mobilization requires further studies.
PMID: 19785055 [PubMed - in process]
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Dasatinib and chronic myeloid leukemia: two-year follow-up in eight clinical trials.
Clin Lymphoma Myeloma. 2009 Dec;9(6):417-24
Authors: Pavlů J, Marin D
Imatinib is currently regarded as the best initial treatment for patients with chronic myeloid leukemia (CML). However, a significant proportion of patients who relapse, fail to respond, or develop intolerance might benefit from the use of second-generation tyrosine kinase inhibitors. In this review, we report the 2-year results in 8 clinical trials involving more than 2000 patients treated with dasatinib (phases I-III). Patients with CML who had failed to respond or were intolerant to imatinib were enrolled in a phase I trial. The positive results emanating from this study led to a series of 5 phase II trials known as START (SRC/ABL tyrosine kinase inhibition activity: research trials of dasatinib). In addition, 2 phase III dose-optimization trials have now been completed. These trials demonstrate that dasatinib offers clinical benefit to patients resistant or intolerant to imatinib, with a well-described and manageable adverse event profile.
PMID: 19951880 [PubMed - indexed for MEDLINE]
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[Molecular remission of chronic myeloid leukaemia in a patient with hepatitis and a second kidney transplant]
Nefrologia. 2009;29(6):604-7
Authors: Castillo-Rama M, Grande C, Martínez-Sanchez P, Olavarria E, Marín D, Paz-Artal E, Andrés A, Morales JM
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of cells in the myeloid line, expressing the BCR-ABL fusion protein responsible for the oncogenic effect of CML. The current frontline therapy in CML is the BCR-ABL tyrosine kinase inhibitor, Imatinib. Although this drug has been shown to improve survival in CML patients, its role in the context of a transplant setting has not been widely described in the literature. We report on the long term molecular remission of CML in a 55 year old man with a second renal transplant who is hepatitis C virus positive, and has associated cardiovascular and immunological risk factors.
PMID: 19936007 [PubMed - indexed for MEDLINE]
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A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells.
Leukemia. 2010 Jan;24(1):44-50
Authors: Rix U, Remsing Rix LL, Terker AS, Fernbach NV, Hantschel O, Planyavsky M, Breitwieser FP, Herrmann H, Colinge J, Bennett KL, Augustin M, Till JH, Heinrich MC, Valent P, Superti-Furga G
Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.
PMID: 19890374 [PubMed - indexed for MEDLINE]
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Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib: weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history.
Leukemia. 2010 Jan;24(1):6-12
Authors: Jabbour E, Hochhaus A, Cortes J, La Rosée P, Kantarjian HM
For patients with chronic myeloid leukemia who become or are inherently resistant to imatinib therapy, including dose escalation, several important factors must be considered when deciding which strategy to attempt next. The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib offer improved potency and a high likelihood of success for these patients. Overall, the efficacy data are comparable for these two agents, and so physicians should consider the BCR-ABL mutation profile and the patient’s history to make an educated decision on the best choice. Only a few BCR-ABL mutations seem to be less responsive to either nilotinib or dasatinib and it is recommended to choose the second-line TKI that has shown clinical activity against the specific mutation in these cases. For patients with all other mutations, and for patients with no mutations, it is recommended to choose the second-generation TKI based on the patient’s disease history. It is important to choose an agent that minimizes the likelihood of exacerbating the patient’s past tolerability issues to imatinib, or comorbid conditions. Here, we propose a treatment algorithm for imatinib-resistant patients based on BCR-ABL mutation status and patient history.
PMID: 19798095 [PubMed - indexed for MEDLINE]
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Low or undetectable numbers of Philadelphia chromosome-positive leukemic stem cells (Ph(+)CD34(+)CD38(neg)) in chronic myeloid leukemia patients in complete cytogenetic remission after tyrosine kinase inhibitor therapy.
Leukemia. 2010 Jan;24(1):219-22
Authors: Mustjoki S, Rohon P, Rapakko K, Jalkanen S, Koskenvesa P, Lundán T, Porkka K
PMID: 19776759 [PubMed - indexed for MEDLINE]
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[Glivec induced autoimmune hepatitis]
Gastroenterol Clin Biol. 2009 Oct-Nov;33(10-11):982-4
Authors: Charier F, Chagneau-Derrode C, Levillain P, Guilhot F, Silvain C
PMID: 19765927 [PubMed - indexed for MEDLINE]
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