Posted by rob on August 25, 2009 under Uncategorized | 
Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells.
Mol Oncol. 2009 Jul 29;
Authors: Hamid R, Brandt SJ
Transforming growth-interacting factor (TGIF) is a homeobox transcriptional repressor that has been implicated in holoprosencephaly and various types of cancer. TGIF is expressed in hematopoietic stem cells and modulates TGF-beta and retinoic acid (RA) signaling, both of which play an important role in hematopoiesis. We recently reported that TGIF’s levels correlate inversely with survival in patients with acute myelogenous leukemia. Here we present the first direct evidence of a role for TGIF in myelopoiesis. We used short hairpin RNA interference to define the effects of TGIF knockdown on proliferation and differentiation of myeloid leukemia-derived cell lines. Decreased TGIF expression resulted in reduced proliferation and differentiation and lower expression of CEBPbeta, CEBPepsilon, PU.1 and RUNX1, key myeloid transcription factors. Furthermore, TGF-beta signaling was increased and RA signaling was decreased. Further insights into the molecular basis of TGIF’s effects were provided by a genome-wide chromatin immunoprecipitation-based elucidation of TGIF target genes. Together, these data suggest that TGIF has an important role myelopoiesis and may regulate the balance between proliferation and differentiation. Reduced TGIF expression could tip the balance toward quiescence thus providing progenitor as well as hematopoietic stem cells protection from anti-cycle agents.
PMID: 19699159 [PubMed - as supplied by publisher]
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Posted by rob on August 22, 2009 under Uncategorized |
Second unrelated cord blood transplantation using a reduced-intensity conditioning regimen combined with gemtuzumab ozogamicin in patients with relapsed acute myelogenous leukemia.
Int J Hematol. 2009 Aug 22;
Authors: Yamauchi T, Mori Y, Miyamoto T, Kamezaki K, Aoki T, Yamamoto A, Takenaka K, Iwasaki H, Harada N, Nagafuji K, Teshima T, Akashi K
Gemtuzumab ozogamicin (GO) is an effective molecular-targeted agent for CD33-positive acute myelogenous leukemia (AML) patients who are resistant to conventional chemotherapy. Recent prospective trials have revealed the safety and efficacy of GO as part of conditioning following allogeneic bone marrow or peripheral blood stem cell transplantation (SCT). We report here for the first time three AML cases that relapsed after allogeneic SCT and underwent unrelated cord blood transplantation (UCBT) following reduced-intensity conditioning (RIC) comprising fludarabine, melphalan, and low-dose total body irradiation combined with GO. Primary neutrophil engraftment occurred in all cases, while recovery of platelet count was delayed. Only one case of reversible hepatic sinusoidal obstruction syndrome was documented. Non-relapse mortality at day 100 was not documented. Notably, one patient who responded to GO survived for 6 months after UCBT in remission with excellent performance status, while the remaining cases relapsed early. These data suggest that GO may be safely combined with RIC for UCBT after previous allogeneic SCT.
PMID: 19697098 [PubMed - as supplied by publisher]
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Chronic myelogenous leukemia and benzene exposure: a systematic review and meta-analysis of the case-control literature.
Chem Biol Interact. 2009 Aug 17;
Authors: Lamm SH, Engel A, Joshi KP, Byrd D, Chen R
Benzene exposure is well demonstrated as a cause of acute myelogenous leukemia, but not of chronic myelogenous leukemia. Previous literature reviews based on case series and cohort studies have not shown an association. We have now conducted a literature search for case-control studies that examine the association between benzene exposure and chronic myelogenous leukemia. Six case-control studies have been found. These derive from occupational groups, cancer registries, and a clinical laboratory. Their exposure ascertainments are all based on job histories, job-exposure matricies, or industrial hygiene data. The odds ratios (ORs) for individual studies range from 0.73 to 1.2. The pooled OR is 1.003 with 95% confidence interval (CI) of 0.94-1.07 (p = 0.98) for both a fixed effects model and a random effects model. The case-control literature indicates that chronic myelogenous leukemia does not appear to be related to benzene exposure.
PMID: 19695237 [PubMed - as supplied by publisher]
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Usefulness of classic cytogenetic testing compared to fluorescence in situ hybridization in genetic diagnosis of 58 patients with myelodysplastic syndromes.
Pol Arch Med Wewn. 2009 Jun;119(6):366-72
Authors: Skonieczka K, Duszeńko E, Wyrowińska E, Haus O
INTRODUCTION: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal diseases of pluripotent hematopoietic stem or progenitor cells. MDS are characterized by ineffective hematopoiesis, increased apoptosis, peripheral blood cytopenias, and propensity to evolve into acute myelogenous leukemia. OBJECTIVES: The aim of our investigation was to compare the usefulness of classic cytogenetics and fluorescence in situ hybridization (FISH) to detect chromosome aberrations in myelodysplastic syndromes. PATIENTS AND METHODS: The study was carried out in a group of 58 patients with MDS. G-banding using trypsin and Giemsa (GTG banding) and FISH with a panel of five molecular probes for aberrations with prognostic significance in MDS (cen7/8, 5q31, 7q22/q35, 17p13, 20q13.3) were performed on bone marrow cells. RESULTS: The use of GTG technique allowed to detect chromosome aberrations in 25 (43.1%) subjects. However, the additional use of FISH showed the presence of aberrations also in additional 10 (17.2%) patients, which shifted 11 patients from one cytogenetic category to another. CONCLUSIONS: The use of FISH with MDS probe panel beside classic cytogenetics improves detection of chromosome aberrations, and also stratification of MDS patients to prognostic groups. Both methods should be used simultaneously in every genetically diagnosed MDS patient.
PMID: 19694218 [PubMed - in process]
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Posted by rob on August 21, 2009 under Uncategorized |
Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors.
Target Oncol. 2009 Apr;4(2):99-105
Authors: Kelly K, Swords R, Mahalingam D, Padmanabhan S, Giles FJ
Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukemia (CML) and are increasingly used in other malignancies. Despite the apparent selectivity of these agents significant side effects can occur mainly due to off target kinase inhibition. Clinical consequences of serosal inflammation, including pleural and pericardial effusions, have emerged as a frequent adverse event associated with dasatinib while occurring much less frequently during imatinib and nilotinib therapy. The pathogenesis is uncertain but may involve inhibition of platelet derived growth factor or expansion of cytotoxic T and natural killer cells. The development of serosal inflammation with dasatinib poses a significant challenge to physicians, as it cannot be predicted, the time of onset is variable, and management frequently requires repeat invasive procedures.
PMID: 19381453 [PubMed - indexed for MEDLINE]
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Posted by rob on under Uncategorized |
Maximum tolerated dose: clinical endpoint for a bygone era?
Target Oncol. 2009 Apr;4(2):143-7
Authors: Takimoto CH
The maximum tolerated dose (MTD) has been the classically recommended phase II dose for cytotoxic chemotherapy anticancer agents. However, the development of molecular targeted therapies with highly specific mechanisms of action has raised questions about the paradigm of dosing at the MTD. Inhibition of the molecular target may occur at dose levels substantially below those producing dose limiting toxicities. The impact of targeted therapies on our dose selection strategies has been immense; however, defining the MTD in phase I oncology trials still provides valuable information for future drug development. But, the MTD should not be selected blindly as the recommended phase II dose for efficacy testing. Optimal dose selection for targeted cancer agents needs to be evaluated using all available information collected during the early stages of drug development. Definition of the optimal dose may need to be deferred until randomized phase II trials can be conducted. Future clinical trail designs in oncology drug development need to reflect this paradigm shift.
PMID: 19377851 [PubMed - indexed for MEDLINE]
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The toxicities of modern targeted therapies: learning from the price of progress.
Target Oncol. 2009 Apr;4(2):65-6
Authors: Giles FJ
PMID: 19357815 [PubMed - indexed for MEDLINE]
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Posted by rob on under Uncategorized |
Leukemia: genetics and prognostic factors.
J Pediatr (Rio J). 2008 Aug;84(4 Suppl):S52-7
Authors: Hamerschlak N
OBJECTIVE: To present the implications of genetics, particularly of cytogenetic techniques, for the diagnosis and prognosis of leukemia. SOURCES: A survey of articles selected from MEDLINE, American Society of Hematology educational programs, the CAPES web portal, the National Comprehensive Cancer Network and textbook chapters. SUMMARY OF THE FINDINGS: Since the discovery in 1960 by Peter C. Nowel and David Hungerford of the 9:22 translocation (the Philadelphia chromosome), genetics has come to play an important role in hematology, in this case making it possible to diagnose chronic myeloid leukemia and opening doors to research avenues for the whole field of oncology. One point of great interest refers to the implications of these findings for the prognosis of a range of types of leukemia. In acute myeloid leukemia, the karyotype is of fundamental importance to postremission treatment decisions, and molecular factors determine the treatment of individuals with normal karyotypes. In chronic myeloid leukemia, clonal evolution is associated with progression to the blast crisis. Patients on imatinib who cease responding may have mutations on their ABL gene. Finally, in acute lymphoblastic leukemia, factors such as hyperdiploidy and t 12:21 are associated with good prognosis, whereas carriers of t 4:11 and t 9:22 are considered high risk patients. CONCLUSIONS: Genetics has come to stay as far as hematology and, in particular, the management of leukemia and its prognostic factors are concerned. These tests should always be carried out and the appropriate treatment adopted in the light of their results, so that optimal patient outcomes can be achieved.
PMID: 18830516 [PubMed - indexed for MEDLINE]
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Posted by rob on August 20, 2009 under Uncategorized |
Abstract: Lineage switch is a very rare event in blastic crisis of chronic myelogenous leukemia (CML-BC). To our knowledge, only three cases of lineage switch between lymphoid and myeloid/myelomonocytic lineages have been reported in the literature. Here, we report a novel case of imatinib-resistant CML-BC, in which the blast lineage switched from biphenotypic to B-lymphoid. (Source: Leukemia Research)
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Posted by rob on under Uncategorized |
Chronic myelogenous leukemia (CML) is classified as one of the myeloproliferative disorders, and is known to have a triphasic clinical course. Blast crisis is a critical phase resembling acute leukemia. First and second generation oral tyrosine kinase inhibitors target the pathogenesis of CML. Extra-medullar manifestation is a known complication of acute lymphoblastic leukemia (ALL) and lymphoid blast crisis of CML. The central nervous system is a sanctuary site of relapse after chemotherapy or hematopoietic stem cell transplantation. We now report an isolated CNS lymphoid blast crisis in a patient with CML on dasatinib. (Source: Leukemia Research)
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In conclusion, the study reveals that the ability of C. rotundus to inhibit the enzyme xanthine oxidase (XO), the lipid peroxidation and to exert apoptotic effect, may explain possible mechanisms by which C. rotundus exhibits its health benefits.
PMID: 19446539 [PubMed - indexed for MEDLINE] (Source: Chemico-Biological Interactions)
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Posted by rob on under Uncategorized |
[Study of deletion of derivative chromosome 9 in patients with Ph+ chronic myeloid leukemia]
Zhonghua Xue Ye Xue Za Zhi. 2006 Mar;27(3):183-6
Authors: Wu W, Xue YQ, Wu YF, Pan JL, Shen J
OBJECTIVE: To determine the frequency of the derivative 9 [der(9)] deletion among chronic myeloid leukemia (CML) patients with classic and variant Ph translocations, and assess the correlation between this deletion and clinical prognosis. METHODS: Cytogenetic analysis of bone marrow cells was performed by direct method and/or 24 h culture method. RHG banding was used for karyotype analysis. Dual-color and dual-fusion DNA probe was used to perform FISH for investigating the deletion of der(9) in Ph+ CML patients. RESULTS: Cytogenetics studies showed typical Ph translocation in 76/105 and variant Ph translocation in 29/105 cases. Interphase-FISH studies showed deletion of der(9) in 12 (15.8%) of 76 patients with classic Ph translocation and in 4 (13.7%) of 29 patients with variant translocation. The frequency of deletion was similar in classic and variant translocations (P > 0.05). When the deletion was seen in the patient, it was present in all the Ph+ metaphases and nuclei. In 3 patients there were mixed cell populations with either 5′-abl or 3′-bcr deletion and all the 3 patients had both 5′-abl and 3′-bcr deletion. The median survival time of patients with deletion was significantly shorter than those without deletion (34 months vs 76 months; P < 0.05). CONCLUSION: Deletion of der(9) is seen in about 1/6 of Ph+ CML patients in our study on Chinese CML patients, Ph+ CML patients with the deletion have shorter median survival time than those without it, indicating that it is a poor prognostic index.
PMID: 16792921 [PubMed - indexed for MEDLINE]
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Posted by rob on August 19, 2009 under Uncategorized |
Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: comparing plasma levels of responders and non-responders.
Eur J Clin Pharmacol. 2009 Jun;65(6):545-9
Authors: Singh N, Kumar L, Meena R, Velpandian T
PURPOSE: Imatinib mesylate is used as first line therapy in the treatment of chronic myeloid leukaemia. This study was designed to study the correlation of plasma levels of imatinib with response to the therapy. METHODS: A total of 40 chronic myeloid leukaemia patients in the chronic phase of the disease were recruited and placed into two groups of 20 patients: imatinib responders and imatinib non-responders, respectively. Each blood sample was taken 24 h after and immediately prior to taking a 400 mg oral dose of imatinib. Drug levels were detected by high-performance liquid chromatography. RESULTS: The mean plasma imatinib levels in the imatinib non-responders were significantly lower than those in the imatinib responders (0.70 vs. 2.34 microM, respectively; p = 0.002). CONCLUSIONS: Plasma levels of imatinib were correlated with response to the therapy, so routine monitoring of the therapeutic levels of the drug should be carried out specifically in treatment-resistant cases for determining dose escalation.
PMID: 19214491 [PubMed - indexed for MEDLINE]
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Posted by rob on under Uncategorized |
Autoantibody-mediated agranulocytosis in association with chronic GVHD.
Bone Marrow Transplant. 2008 Sep;42(5):359-60
Authors: Ruck S, Hilgendorf I, Müller-Hilke B, Kiefel V, Junghanss C, Freund M, Greinix H, Wolff D
PMID: 18574447 [PubMed - indexed for MEDLINE]
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Posted by rob on under Uncategorized |
Late-onset pneumatosis cystoides intestinalis associated with non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation.
Int J Hematol. 2008 Jul;88(1):116-8
Authors: Suzuki HI, Izutsu K, Watanabe T, Oshima K, Kanda Y, Motokura T, Chiba S, Kurokawa M
PMID: 18560752 [PubMed - indexed for MEDLINE]
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Relapse of chronic myeloid leukemia-chronic phase 14 years after allogeneic hematopoietic stem cell transplantation.
Int J Hematol. 2008 Jul;88(1):119-20
Authors: Akahane D, Ito Y, Sumi M, Tauchi T, Kimura Y, Ohyashiki K
PMID: 18512116 [PubMed - indexed for MEDLINE]
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Posted by rob on August 18, 2009 under Uncategorized |
Knocking-down cyclin A(2) by siRNA suppresses apoptosis and switches differentiation pathways in K562 cells upon administration with doxorubicin.
PLoS One. 2009;4(8):e6665
Authors: Wang X, Song Y, Ren J, Qu X
Cyclin A(2) is critical for the initiation of DNA replication, transcription and cell cycle regulation. Cumulative evidences indicate that the deregulation of cyclin A(2) is tightly linked to the chromosomal instability, neoplastic transformation and tumor proliferation. Here we report that treatment of chronic myelogenous leukaemia K562 cells with doxorubicin results in an accumulation of cyclin A(2) and follows by induction of apoptotic cell death. To investigate the potential preclinical relevance, K562 cells were transiently transfected with the siRNA targeting cyclin A(2) by functionalized single wall carbon nanotubes. Knocking down the expression of cyclin A(2) in K562 cells suppressed doxorubicin-induced growth arrest and cell apoptosis. Upon administration with doxorubicin, K562 cells with reduced cyclin A(2) showed a significant decrease in erythroid differentiation, and a small fraction of cells were differentiated along megakaryocytic and monocyte-macrophage pathways. The results demonstrate the pro-apoptotic role of cyclin A(2) and suggest that cyclin A(2) is a key regulator of cell differentiation. To the best of our knowledge, this is the first report that knocking down expression of one gene switches differentiation pathways of human myeloid leukemia K562 cells.
PMID: 19684852 [PubMed - in process]
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Activity of FB2, a novel dual Abl/Src tyrosine kinase inhibitor, against imatinib-resistant chronic myeloid leukemia in vivo and in vitro.
Leuk Lymphoma. 2009 Mar;50(3):437-46
Authors: Liu H, Li H, Feng Z, Tai J, Meng Y, Wang H, Xin H, Zhang S, Zuo M, Zhang Y, Chen X
FB2 is a novel Abl/Src dual tyrosine kinase inhibitor which is designed to overcome imatinib resistance. Besides imatinib-sensitive cell lines (K562), FB2 significantly inhibited the growth of imatinib-resistant cell lines of different resistance mechanisms (K562/G5.0 and K562/G01), and decreased the expression of autophosphorylation of Bcr/Abl, c-Src and Lyn kinases on them. It also inhibited the proliferation of Src over activated cells DU145 and MDA-MB-231. Furthermore, FB2 potently prolonged the survival time of non-obese diabetic/severe combined immunodeficient mice harboured K562/G5.0 cells. These results indicated that FB2, an Abl/Src dual tyrosine kinase inhibitor, is a promising candidate for imatinib-resistant CML and Src over activated cancer.
PMID: 19347730 [PubMed - indexed for MEDLINE]
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Posted by rob on August 16, 2009 under Uncategorized |
Curcumin, a natural product isolated from the plant Curcuma longa, has a diverse range of molecular targets that influence numerous biochemical and molecular cascades. Curcumin has been shown to inhibit nuclear factor [kappa]B (NF-[kappa]B) activation at several steps in the NF-[kappa]B signaling pathways and thereby controls numerous NF-[kappa]B-regulated genes involved in various diseases. In the present study, we investigated the effect of curcumin pretreatment on 84 tumor necrosis factor-[alpha] (TNF-[alpha])-activated genes of NF-[kappa]B pathways in K562 cells, using a real-time PCR array. Our results show that transcription of 29 NF-[kappa]B-related mRNAs was significantly downregulated (CARD4, CCL2, CD40, CSF2, F2R, ICAM1, IKBKB, IKBKE, IL1A, IL1B, IL6, IL8, IRAK2, MALT1, MAP3K1, M…
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Posted by rob on August 15, 2009 under Uncategorized |
Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia.
Expert Opin Investig Drugs. 2009 Sep;18(9):1333-49
Authors: Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Manzoli L, McCubrey JA
BACKGROUND: The PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation and survival not only under physiological conditions but also in a variety of tumor cells. Therefore, the PI3K/Akt/mTOR axis may be a critical target for cancer therapy. OBJECTIVE: This review discusses how PI3K/Akt/mTOR signaling network is constitutively active in acute myelogenous leukemia (AML), where it strongly influences proliferation, survival and drug-resistance of leukemic cells, and how effective targeting of this pathway with pharmacological inhibitors, used alone or in combination with existing drugs, may result in suppression of leukemic cell growth, including leukemic stem cells. METHODS: We searched the literature for articles dealing with activation of this pathway in AML and highlighting the efficacy of small molecules directed against the PI3K/Akt/mTOR signaling cascade. CONCLUSIONS: The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.
PMID: 19678801 [PubMed - in process]
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