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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
[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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
[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]
More
Posted by rob on January 25, 2010 under Uncategorized |
Nuclear Factor-kappaB Signaling: A Contributor in Leukemogenesis and a Target for Pharmacological Intervention in Human Acute Myelogenous Leukemia.
Crit Rev Oncog. 2009;15(1):1-36
Authors: Reikvam H, Olsnes AM, Gjertsen BT, Ersvar E, Bruserud O
Acute myeloid leukemia (AML) is an aggressive malignancy with only 40 – 50% long-term survival even for younger patients who can receive the most aggressive therapy. For elderly patients who only receive palliative treatment, the median survival is only 2-3 months. Inhibition of the nuclear factor-kappaB (NF-kappaB) transcription factor family is one of the therapeutic strategies that are considered in AML. NF-kappaB is an important regulator of several biological processes that are involved in leukemogenesis, including proliferation differentiation, autophagy, and apoptosis. Constitutive NF-kappaB activation has been detected in AML cells and NF-kappaB inhibition is therefore a possible therapeutic strategy in AML. Multiple pharmacological agents have shown inhibitory effects against NF-kappaB signaling pathways, including proteasome inhibitors as well as the more-specifc agents that are directed against various steps of this signaling pathway. Recent studies strongly suggest that primary human AML cells (including AML stem cells) are susceptible to NF-kappaB inhibition, but this therapeutic approach should possibly be combined with other therapeutic agents to achieve a combined effect both on NF-kappaB transcriptional activity, tumor suppressor-induced signaling, and stress-induced pathways. The clinical documentation with regard to the effciency and safety of NF-kappaB inhibition is still limited, but experimental evidence strongly suggests that NF-kappaB inhibition should be further investigated in human AML.
PMID: 20092433 [PubMed - in process]
More
Posted by rob on January 22, 2010 under Uncategorized |
Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70.
PLoS One. 2010;5(1):e8719
Authors: Banerjee Mustafi S, Chakraborty PK, Raha S
BACKGROUND: Resveratrol is known to downregulate the high endogenous level of Heat shock protein 70 (Hsp70) in Chronic Myelogenous Leukemia (CML) K562 cells and induce apoptosis. Since Heat Shock Factor 1 (HSF1) controls transcription of Hsp70, we wanted to probe the signaling pathways responsible for transcriptional activation of HSF1. METHODOLOGY/PRINCIPAL FINDINGS: Cells exposed to 40microM Resveratrol rapidly abolished serine473 phosphorylation of Akt and significantly reduced its kinase activity. Inactivation of Akt pathway by Resveratrol subsequently blocked serine9 phosphorylation of Gsk3beta. Active non-phosphorylated Gsk3beta rendered HSF1 transcriptionally inactive and reduced Hsp70 production. Blocking PI3K/Akt activity also demonstrated similar effects on Hsp70 comparable to Resveratrol. Inactivation of Gsk3beta activity by inhibitors SB261763 or LiCl upregulated Hsp70. Resveratrol significantly modulated ERK1/2 activity as evident from hyper phosphorylation at T302/Y304 residues and simultaneous upregulation in kinase activity. Blocking ERK1/2 activation resulted in induction of Hsp70. Therefore, increase in ERK1/2 activity by Resveratrol provided another negative influence on Hsp70 levels through negative regulation of HSF1 activity. 17-allylamino-17-demethoxygeldanamycin (17AAG), a drug that inhibits Hsp90 chaperone and degrades its client protein Akt concomitantly elevated Hsp70 levels by promoting nuclear translocation of HSF1 from the cytosol. This effect is predominantly due to inhibition of both Akt and ERK1/2 activation by 17AAG. Simultaneously treating K562 with Resveratrol and 17AAG maintained phosho-ERK1/2 levels close to untreated controls demonstrating their opposite effects on ERK1/2 pathway. Resveratrol was found not to interfere with Bcr-Abl activation in K562 cells. CONCLUSION/SIGNIFICANCE: Thus our study comprehensively illustrates that Resveratrol acts downstream of Bcr-Abl and inhibits Akt activity but stimulates ERK1/2 activity. This brings down the transcriptional activity of HSF1 and Hsp70 production in K562 cells. Additionally, Resveratrol can be used in combination with chemotherapeutic agents such as 17AAG, an Hsp90 inhibitor reported to induce Hsp70 and hence compromise its chemotherapeutic potential.
PMID: 20090934 [PubMed - in process]
More
Posted by rob on under Uncategorized |
A Review of Kinases Implicated in Pancreatic Cancer.
Pancreatology. 2010 Jan 15;9(6):738-754
Authors: Giroux V, Dagorn JC, Iovanna JL
The current 5-year survival rate of pancreatic cancer is about 3% and the median survival less than 6 months because the chemotherapy and radiation therapy presently available provide only marginal benefit. Clearly, pancreatic cancer requires new therapeutic concepts. Recently, the kinase inhibitors imatinib and gefitinib, developed to treat chronic myelogenous leukaemia and breast cancer, respectively, gave very good results. Kinases are deregulated in many diseases, including cancer. Given that phosphorylation controls cell survival signalling, strategies targeting kinases should obviously improve cancer treatment. The purpose of this review is to summarize the present knowledge on kinases potentially usable as therapeutic targets in the treatment of pancreatic cancer. All clinical trials using available kinase inhibitors in monotherapy or in combination with chemotherapeutic drugs failed to improve survival of patients with pancreatic cancer. To detect kinases relevant to this disease, we undertook a systematic screening of the human kinome to define a ’survival kinase’ catalogue for pancreatic cells. We selected 56 kinases that are potential therapeutic targets in pancreatic cancer. Preclinical studies using combined inhibition of PAK7, MAP3K7 and CK2 survival kinases in vitro and in vivo showed a cumulative effect on apoptosis induction. We also observed that these three kinases are rather specific of pancreatic cancer cells. In conclusion, if kinase inhibitors presently available are unfortunately not efficient for treating pancreatic cancer, recent data suggest that inhibitors of other kinases, involved more specifically in pancreatic cancer development, might, in the future, become interesting therapeutic targets. and IAP.
PMID: 20090395 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Herpetic geometric glossitis: Acyclovir resistant case in a patient with acute myelogenous leukemia.
Indian J Pathol Microbiol. 2010 Jan-Mar;53(1):133-4
Authors: Pereira CM, Souza CA, Correa ME
Herpes simplex virus (HSV) infections in an immunocompromised host may be atypical in location and morphology. Lesions are more extensive and aggressive, slow healing or nonhealing and extremely painful. Intraoral lesions are ulcerative and may involve any intraoral, oropharyngeal, or esophageal site. Herpetic geometric glossitis is a recently described form of lingual HSV infection in an immunocompromised patient. It was described as ulcer on the dorsum of the tongue sensitive for acyclovir therapy. A patient is presented with acute myelogenous leukemia that developed herpetic geometric glossitis which was acyclovir resistant.
PMID: 20090244 [PubMed - in process]
More
Posted by rob on under Uncategorized |
Is there any relationship between imatinib mesylate medication and hypothalamic-pituitary-adrenal axis dysfunction?
Int J Clin Pract. 2010 Jan;64(1):45-50
Authors: Bilgir O, Kebapcilar L, Bilgir F, Sarì I, Oner P, Karaca B, Alacacioglu I
SUMMARY BACKGROUND: Imatinib mesylate [tyrosine kinase (TK) inhibitor] is a novel medication in the treatment of chronic myelogenous leukaemia (CML). TK is also essential in hypothalamo-pituitary-adrenal (HPA) axis. PURPOSE: The aim of this study was to evaluate HPA axis in patients treated with imatinib. Twenty-five patients were included in this study. METHODS: Glucagon stimulation test (GST) and low-dose (1 microg) adrenocorticotropin test (LDSST) were used to assess the HPA gland axis. Results: Seventeen (68%) subjects had impaired peak response when a cortisol cut-off value is accepted as 500 nmol/L. Twelve (48%) out of 17 subjects also failed to show a response to LDSST. Therefore, 12 patients (48%) were defined as HPA deficient. Only two of these 25 patients had morning serum cortisol < 200 nmol/l (7.22 microg/dl), and failed the GST and/or LDSST, indicating that the majority had partial glucocorticoid deficiency. If the cut-off presume for LDSST is from 500 to 600 nmol/l, 16 patients (64%) would have failed both the GST and LDSST. Conclusion: Our results indicate an increased prevalence of subclinical glucocorticoid deficiency in patients receiving imatinib mesylate for CML. Therefore under stressed conditions, such as intercurrent illness state, overt and untreated partial glucocorticoid deficiency in CML patients become life threatening.
PMID: 20089016 [PubMed - in process]
More
Posted by rob on under Uncategorized |
c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration.
FEBS Lett. 2010 Jan 4;584(1):15-21
Authors: Baruzzi A, Iacobucci I, Soverini S, Lowell CA, Martinelli G, Berton G
Cytoskeleton dynamics are regulated by Src-family tyrosine kinases (SFKs) and c-Abl. We found that the SFK members Hck and c-Fgr regulate tyrosine phosphorylation of c-Abl and c-Abl associates with beta1 integrin-bound Hck or c-Fgr in murine macrophages. Studies with selective inhibitors and cells from SFK-deficient mice showed that c-Abl and SFK regulate migration and activation of the small GTPases Cdc42 and Rac in macrophages. Additionally, human neutrophil chemotactic activity was reduced by c-Abl inhibitors, and neutrophils from chronic myeloid leukaemia patients displayed an increased chemotactic ability. Hence, Src-family kinase and c-Abl cross-talk in the regulation of myeloid cell migration.
PMID: 19903482 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
BK nephropathy in pediatric hematopoietic stem cell transplant recipients.
Pediatr Transplant. 2009 Nov;13(7):913-8
Authors: Verghese PS, Finn LS, Englund JA, Sanders JE, Hingorani SR
BK nephropathy is a known cause of renal insufficiency in kidney transplant recipients. Activation of the polyoma virus may also occur in the native kidneys of non-renal allograft recipients. BK nephropathy has only been reported in a few patients after HCT, most being adult patients, and the single reported pediatric case had evidence of hemorrhagic cystitis. The response to antiviral therapy also seems to differ widely. Here, we describe two cases of BK nephropathy in the native kidneys of HCT recipients exposed to high levels of immunosuppression because of GVHD. Neither of our patients had any evidence of hemorrhagic cystitis. We present definitive renal pathology and detailed chronological evidence of the rising serum creatinine with simultaneous serum and urine BK PCR titers. In one of our cases, antiviral therapy did not seem beneficial as documented by continued renal dysfunction and elevated serum/urine BK PCR titers. Based on our report, intense immunosuppression in pediatric HCT recipients seems to be involved in the activation of BK virus and BK nephropathy should be suspected even in the absence of hematuria in HCT recipients with unexplained renal dysfunction.
PMID: 19067914 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Influences of interferon-alpha on expression of Th cytokines and CCR7 in dendritic cells from patients with chronic myeloid leukemia in vitro.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008 Apr;16(2):401-5
Authors: Zhao WL, Chai YH, He HL, Wei XC, Wang T, Xing PN, Li MS
This study was aimed to investigate the influences of interferonalpha (IFN-alpha) on expressions of CCR7, interleukin10 (IL-10) and IL-12p70 in dendritic cells (DCs) from patients with chronic myeloid leukemia (CML). In addition to stem cell factor (SCF), granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha) and IL-4, IFN-alpha was added to the serum-free medium of DCs. After culture for 10-14 days, phenotypes and function of CML-DCs were evaluated respectively by flow cytometry and methyl thiazolyl tetrazolium (MTT) assay. Chromosome of DCs was analyzed by displaying G banding assay. The concentrations of IL-10 and IL-12P70 in supernatants were evaluated by enzyme-linked immunosorbent assay (ELISA). The results showed that the expressions of CD40, CD83, CD86 and CCR7 and the OD value in allogeneic mixed-lymphocyte reaction (MLR) in group with IFN-alpha (300 U/ml) were twice as high as those in group without IFN-alpha. The percentage of Ph1 positive cells and concentrations of IL-10 and IL-12 P70 were reduced in group with IFN-alpha. It is concluded that the defective phenotypes and functions of CML-DCs can be recruited partly by IFN-alpha. The mechanism may lie in the facts that expression of CCR7 and co-stimulatory molecules is promoted and the inhibitory effect of IL-10 on CML-DCs is relieved partly through the regulation of IFN-alpha.
PMID: 18426674 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
[Research advance on molecular genetics of CML blast crisis]
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008 Feb;16(1):217-21
Authors: Zhu HQ, Zhang S, Liu XL
Philadelphia (Ph) chromosome at (9; 22) reciprocal chromosomal translocation producing BCR-ABL fusion gene, emerges in almost all patients with chronic myeloid leukemia (CML). The protein product of BCR-ABL is a constitutively active tyrosine kinase that drives the abnormal proliferation of CML cells. Blast crisis (BC) is the terminal phase of CML, which is often associated with additional chromosomal and molecular secondary changes. Although the mechanisms responsible for transition of CML chronic phase (CP) into BC remain poorly understood, ample evidence suggests that it depends on synergy of BCR/ABL with other genes dysregulated during disease progression, and signaling pathways are abnormally activated by BCR/ABL. With the application of imatinib, a ABL-specific tyrosine kinase inhibitor, its remarkable therapeutic effects suggest that blast crisis transition will be postponed in most patients with CML. Rate of cumulative best response in CML-CP patients from the IRIS trial after 5 years are 98% for complete hematologic response, 92% for major cytogenetic response and 87% for complete cytogenetic response. However, a minority of CML-CP patients and most patients in progression either fail or respond suboptimally to imatinib. There are many distinct patterns of resistance, and ABL kinase mutations is a common finding associated with clinical resistance. Dasatinib and nilotinib can restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase. This review illustrates the molecular mechanisms underlying transition to CML-BC, also addresses oneself to how and why imatinib resistance occurs.
PMID: 18315935 [PubMed - indexed for MEDLINE]
More
