Posted by rob on March 13, 2011 under Uncategorized | 
AbstractBcr?Abl activates various signaling pathways in chronic myelogenous leukemia (CML) cells. The proliferation of Bcr?Abl transformed cells is promoted by c?Myc through the activation of Akt, JAK2 and NF??B. However, the mechanism by which c?Myc regulates CML cell proliferation is unclear. In the present study, we investigated the role of thanatos?associated protein 11 (THAP11), which inhibits c?Myc transcription, in CML cell lines and in hematopoietic progenitor cells derived from CML patients. The induction of THAP11 expression by Abl kinase inhibitors in CML cell lines and in CML?derived hematopoietic progenitor cells resulted in the suppression of c?Myc. In addition, over?expression of THAP11 inhibited CML cell proliferation. In colony forming cells derived fr…
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The high school junior’s life was turned upside down. But she was determined to not fall into depression.My life drastically changed two weeks into my junior year of high school, when I was diagnosed with chronic myelogenous leukemia, a rare blood cancer. (Source: L.A. Times – Health)
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Azacitidine has limited activity in ‘real life’ patients with MDS and AML: a single centre experience.
Hematol Oncol. 2011 Mar 8;
Authors: Ozbalak M, Cetiner M, Bekoz H, Atesoglu EB, Ar C, Salihoglu A, Tuzuner N, Ferhanoglu B
Myelodysplastic syndrome (MDS) represents a heterogeneous group of potentially malignant diseases of bone-marrow stem cells. Acute myelogenous leukaemia (AML) is an inevitable outcome for many patients with MDS. Azacitidine has been reported to result in comparably higher response rates and improved survival than other treatment strategies. In this retrospective study, we report the results on 25 ‘real life’ patients with MDS, CMML or AML treated with azacitidine between 2005 and 2009. All patients fulfilled the World Health Organization criteria for MDS and AML. No eligibility criteria other than diagnosis were considered. Complete response (CR) rate was observed in three of the 25 ‘real life’ patients (12%) with a median duration of CR of 5 months (4-6 months). Seven patients (28%) had mono- or bi-lineage haematologic improvement and 15 patients (60%) showed neither morphologic nor haematologic response. Among 17 non-AML patients, the median time from onset of Aza-C treatment to AML transformation was 10 months (4-15 months). Overall death rate was 72%. All of the eight AML patients died. The death rate under Aza-C among non-AML patients was 59%. Unlike the results of the clinical trials, our data show that Aza-C has a limited activity in ‘real-life’ patients with MDS and AML. It is obvious that Aza-C can induce complete or partial responses in a considerable number of MDS patients but responses are usually not durable as we observed in our patients. Copyright © 2011 John Wiley & Sons, Ltd.
PMID: 21387357 [PubMed - as supplied by publisher]
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Co-expression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia.
Blood. 2011 Mar 8;
Authors: Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK, Blazar BR
Tumor-associated immune suppression can lead to defective T cell-mediated anti-tumor immunity. Here we identified a unique phenotype of exhausted T-cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the co-expression of Tim-3 and PD-1 on CD8+T-cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 co-expression increased during AML progression. PD-1+Tim-3+ CD8+T-cells were deficient in their ability to produce IFN-?, TNF-?, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, upregulated Tim-3 during AML progression and such Tim-3+PD-1- KO CD8+T-cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced Tregulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8+T-cells. Whereas blocking the PD-1/PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing albeit not eliminating both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8+T-cell exhaustion in patients with hematological malignancies such as advanced AML.
PMID: 21385853 [PubMed - as supplied by publisher]
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Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation.
Blood. 2011 Mar 8;
Authors: Mazharian A, Ghevaert C, Zhang L, Massberg S, Watson SP
Dasatinib is an oral potent ATP-competitive inhibitor of Bcr-Abl, cKIT and Src family kinases which exhibits good efficacy in patients with Imatinib-resistant chronic myelogenous leukemia. Dasatinib treatment is associated with mild thrombocytopenia and an increased risk of bleeding but its biological effect on megakaryocytopoiesis and platelet production is unknown. In this study, we show that Dasatinib causes mild thrombocytopenia in mice without altering platelet half-life suggesting that Dasatinib inhibits platelet formation. On the other hand, the number of megakaryocytes in bone marrow of Dasatinib-treated mice is increased and the ploidy of megakaryocytes derived from bone marrow progenitor cells in vitro is elevated in the presence of Dasatinib. Furthermore, a significant delay in platelet recovery following immune-induced thrombocytopenia is observed in Dasatinib-treated mice even though the number of megakaryocytes in bone marrow is increased relative to controls at all time points. Interestingly, migration of megakaryocytes towards a gradient of SDF1? and the formation of proplatelets in vitro are abolished by Dasatinib. We propose that Dasatinib causes thrombocytopenia as a consequence of ineffective thrombopoiesis promoting megakaryocyte differentiation on one hand but impairing megakaryocyte migration and proplatelet formation on the other hand.
PMID: 21385851 [PubMed - as supplied by publisher]
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[A case of myeloid sarcoma in the anterior mediastinum].
Nihon Kokyuki Gakkai Zasshi. 2011 Jan;49(1):25-9
Authors: Yamamoto H, Sanda R, Ota A, Kato M, Takagi Y, Sugino Y
We report a case of myeloid sarcoma in the anterior mediastinum. The patient was a 33-year-old man with a chief complaint of right shoulder pain, right upper limb edema, and cough. Chest contrast-enhanced computed tomography (CT) revealed a partially enhanced anterior mediastinal tumor. A CT-guided biopsy was then performed, and a Hematoxylin-eosin (HE) stain revealed mitosis of tumor cells and other cells, including eosinophils. Immunohistochemical stains with myeloperoxidase, CD34, CD43, CD68 and c-Kit tests were positive for tumor cells. Due to a pathological diagnosis of myeloid sarcoma, he was treated with chemotherapy based on a diagnosis of acute myelogenous leukemia. After complete remission was obtained, the patient visited another hospital to receive an unrelated bone marrow transplantation. Although it rarely occurs as a mediastinal tumor, the prognosis of myeloid sarcoma is unfavorable, and thus should be taken into consideration as a differential diagnosis.
PMID: 21384678 [PubMed - in process]
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Ocular involvement in chronic graft-versus-host disease: therapeutic approaches to complicated courses.
Cornea. 2011 Jan;30(1):107-13
Authors: Koch KR, Joussen AM, Huber KK
Chronic graft-versus-host disease (cGvHD) is a major concomitant phenomenon in recipients of allogeneic hematopoietic stem cell transplantations, affecting multiple organ systems including the eye. Ocular structures, such as lacrimal gland, conjunctiva, and eyelids with meibomian glands, are frequently involved with clinical features ranging from dry eyes and common inflammatory conjunctival disease to severe complications like corneal ulcerations or even perforations. We present 2 patients with complicated courses of ocular cGvHD. In both cases, keratoconjunctivitis sicca refractory to systemic immunosuppressive therapy and to conventional topical treatment resulted in progressive binocular corneal melting and finally repeated perforations. According to our 2 cases and to the current pathophysiological understanding, we discuss possible strategies for the treatment and prevention of ocular cGvHD complications.
PMID: 20847653 [PubMed - indexed for MEDLINE]
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Activity of the potent dual Abl/Src tyrosine kinase inhibitor FB2 against Bcr-Abl positive cell lines in vitro and in vivo.
Leuk Res. 2011 Feb;35(2):237-42
Authors: Yuan X, Zhang Y, Zhang H, Jin J, Li X, Liu H, Feng Z, Chen X
We have previously shown the inhibition of the small-molecule inhibitor FB2 on imatinib-sensitive and resistance CML cell lines with the wild-type Bcr-Abl fusion gene. Here we report the potent and selective antiproliferation on FB2 on transfected Ba/F3 p210 cell lines expressing various isoforms of Bcr-Abl (wild-type, Y253F, T315I). FB2 which orients Bcr-Abl and Src kinase activities, is shown to override imatinib-resistance CML involving Y253F mutation in the Abl kinase domain of the fusion protein except T315I in vivo and in vitro. Thus, we present FB2 that displays potency toward Bcr-Abl and Src as the molecular target, and which could potentially be used to override drug resistance in CML.
PMID: 20739063 [PubMed - indexed for MEDLINE]
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Posted by rob on March 5, 2011 under Uncategorized |
Chronic myelogenous leukemia with mild basophilia as the predominant manifestation at presentation.
Intern Med. 2011;50(5):501-2
Authors: Yasuda H, Aritaka N, Ando J, Hirama M, Komatsu N, Hirano T
Chronic myelogenous leukemia (CML) is a clonal hematological malignancy typically presenting with basophilia and massive proliferation of differentiating myeloid cells. We report an atypical case of CML in which mild basophilia was the sole manifestation at presentation, and the condition persisted for 27 months with no sign of progression. This case reconfirms the importance of basophilia as a clinical manifestation of CML, and BCR-ABL FISH analysis should always be applied to cases of basophilia, even when the basophilia is modest and no other features of CML are present.
PMID: 21372467 [PubMed - in process]
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Two Novel Alkaloids from the Stem of Saprosma hainanense and Their Cytotoxic Activities in Vitro.
Chem Pharm Bull (Tokyo). 2011;59(3):338-40
Authors: Wang L, Chen GY, Han CR, Yuan Y, Yang B, Zhang Y, Wang J, Zhong XQ, Huang X
Two novel alkaloids, saprosmine A (1) and saprosmine B (2), were isolated from the stem of Saprosma hainanense MERR., along with five known alkaloids: marcanine A (3); cleistopholine (4); 4-methoxycarbonyl-5,10-benzogquinolinequinone (5); liriodenine (6); and quinoline (7). The chemical structures were established on the basis of extensive spectroscopic (IR, 1D-NMR, 2D-NMR, MS) data analysies and by comparison with spectroscopic data reported in the literature. Compounds 1 to 6 were evaluated for in vitro cytotoxic activities against the SPC-A-1 (human lung cancer), BEL-7402 (human hepatocellular carcinoma), SGC-7901 (human gastric cancer), and K-562 (human myelogenous leukaemia) cancer cell lines. Compounds 1 and 2 exhibited weak cytotoxic activities against K-562 cells. Compounds 3 and 5 showed cytotoxic activities against all four cancer cell lines.
PMID: 21372415 [PubMed - in process]
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Discontinuation of imatinib may be possible in chronic myelogenous leukemia.
CA Cancer J Clin. 2011 Mar 3;
Authors: Barton MK
PMID: 21372196 [PubMed - as supplied by publisher]
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LITTLE ROCK, Ark. – In an opinion entered Feb. 17, the Arkansas Supreme Court affirmed a verdict against the parents of a child diagnosed with chronic myelogenous leukemia who allege that exposure to organic arsenic from chicken litter spread on farm fields caused the cancer (Mary E. Green, et al. v. George’s Farm Inc, et al., No. 10-26; Ark. Sup.; 2011 Ark. LEXIS 65; See 5/20/08, Page 4).
Full story on lexis.com (Source: LexisNexis® Mealey’s™ Emerging Toxic Torts Legal News)
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Abstract Molecular monitoring is a key component of the management of patients with chronic myeloid leukemia. The current recommendation
is that molecular monitoring be performed in place of cytogenetic assessment when a major molecular response (MMR) is achieved.
With the more potent kinase inhibitors nilotinib and dasatinib now approved as front-line therapy, more patients will achieve
an MMR and will benefit from molecular monitoring. There is a strong correlation between certain BCR-ABL1 levels and the cytogenetic response, which means that molecular monitoring may act as a surrogate for cytogenetic response,
but only if the BCR-ABL1 values are converted to the international reporting scale. Furthermore, improvements in the limit of BCR-ABL1 detection and reduction of in…
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In conclusion, PTEN could modulate
the function of VEGF/VEGFR signaling pathway down-regulation of Akt phosphorylation and that PTEN would be a candidate target
to be addressed for inhibiting angiogenesis along with the treatment of myeloid leukemia.
Content Type Journal ArticlePages 1-9DOI 10.1007/s12032-011-9867-2Authors
Cheng Zhiyong, Department of Hematology, The First Hospital of Baoding, 966 Baihua Road, 050000 Baoding, ChinaLiang Wentong, Department of Hematology, The First Hospital of Baoding, 966 Baihua Road, 050000 Baoding, ChinaYang Xiaoyang, Department of Hematology, Affiliated Haikou Hospital, Central South University, Haikou Municipal Hospital, 43# People’s Road Haidian Island, 5702083 Haikou, ChinaPan Ling, Department of Hematology, West China Hospital, Sichuan Un…
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AbstractDisease overview:Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute leukemia or myelofibrosis.Diagnosis:Diagnosis is based on JAK2 mutation status (PV and ET), serum erythropoietin (Epo) level (PV), and bone marrow histopathology (ET). The presence of a JAK2 mutation and subnormal serum Epo level confirm a diagnosis of PV. Differential diagnosis in ET should include chronic myelogenous leukemia and prefibrotic myelofibrosis.Risk stratification:Current risk stratification in PV and ET is design…
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Abstract Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success.
However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs
as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic
myelogenous leukemia by imatinib, inhibiting the bcr-abl-activated tyrosine kinase and thereby interrupting the signal transduction
pathways that lead to leukemic transformation with impressive survival benefit, has paved the way for this new optimism. Another
success story is the introduction of trastuzumab in breast cancers overexpressing the HER-2 receptor. In contrast, there has
been little progres…
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Abstract The introduction of tyrosine kinase inhibitors (TKIs) has changed the landscape of therapy for chronic myelogenous leukemia
(CML). Once considered an incurable malignancy, CML now has become a manageable chronic condition. Despite the great advances
that imatinib has brought to the treatment of CML, some patients still develop resistance to imatinib and other TKIs, such
as dasatinib and nilotinib. Furthermore, none of the clinically available TKIs is capable of eradicating leukemia stem cells
and therefore curing CML. Several new compounds have been developed in recent years in an attempt to manage TKI-resistant
CML. These include third-generation TKIs (ponatinib, danusertib) and even old compounds such as omacetaxine, which were developed
before imatinib and now …
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This study provides support that FoxO3 is a good biomarker for BCR-ABL-mediated leukemogenesis. Additionally, proteasomal inhibition by bortezomib may be a promising therapeutic option in Philadelphia-positive ALL, where FoxO3 is downregulated.
PMID: 21282974 [PubMed - as supplied by publisher] (Source: Cancer Biology and Therapy)
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