Posted by rob on July 24, 2010 under Uncategorized | 
Ring chromosome 18 abnormality in acute myelogenous leukemia: the clinical dilemma.
J Hematol Oncol. 2010 Jul 22;3(1):25
Authors: Sivendran S, Gruenstein S, Malone AK, Najfeld V
ABSTRACT: The ring chromosome is a circular, structural abnormality composed of either multiple chromosomes or a single chromosome with loss of genetic material at one or both ends. This chromosomal rearrangement is often unstable with frequent recombinations and may be accompanied by either loss or amplification of genetic material.1 Considering that ring chromosomes are rare in acute myelogenous leukemia (AML), it is difficult to risk stratify patient prognosis, particularly when the ring chromosome occurs as the sole abnormality. Here we report a case of a ring chromosome 18 abnormality in a patient with newly diagnosed AML with monocytic differentiation. Cytogenetic analysis demonstrated 46,XY,r(18)(p11q21) karyotype in 19 of 34 evaluated metaphase cells. The patient received induction chemotherapy and subsequent allogeneic cord blood transplant from a sex-matched donor, and remained in hematologic and cytogenetic remission for 120 days post transplant. Soon after, he developed post transplant lymphoproliferative disorder and died of multi-organ failure. Although r(18) chromosomal abnormalities were not classified in the recent updated evidence-and expert opinion-based recommendations for the diagnosis and management of AML (likely due to the small number of reported cases), the patient was treated as high risk with stem cell transplantation. This was based on the unstable nature of the ring chromosome and the poor outcomes described in the literature of patients with sole ring 18 abnormalities.
PMID: 20649984 [PubMed - as supplied by publisher]
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Posted by rob on July 23, 2010 under Uncategorized |
A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects.
Cancer Biol Ther. 2010 Sep 13;10(6)
Authors: Keasey N, Herse Z, Chang S, Liggitt DH, Lay M, Fairman J, Claxton DF
Cationic lipid DNA complex (CLDC) is an immunostimulatory preparation that has significant anti-leukemic effects in multiple murine models of leukemia: BCR-ABL(+) myelogenous leukemia in C3H/HeJ animals and myelomonocytic leukemia in BALB/c mice. Following leukemic challenge, CLDC treatment inhibits tumor cell growth in vivo and extends survival, sometimes resulting in apparent eradication of tumor cells. CLDC induces multiple cytokines including interferon-gamma (IFNgamma), and intravenous treatment results in a more rapid and robust response than subcutaneous treatment. IFNgamma is induced in a dose-dependent manner, and tachyphylaxis results from repeated doses of CLDC. Tachyphylaxis of therapeutic effects is exacerbated at higher doses, thus the optimal survival benefits are seen at intermediate doses. Animals whose leukemia has been successfully treated with CLDC exhibit a survival advantage when faced with a secondary leukemic challenge, suggesting the existence of an adaptive anti-leukemic response. This work demonstrates the effectiveness of CLDC in multiple experimental leukemias and is consistent with a stimulation of a lasting TH(1) anti-leukemic immune response.
PMID: 20647744 [PubMed - as supplied by publisher]
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Occurrences of opportunistic infections in chronic myelogenous leukemia patients treated with imatinib mesylate.
Leuk Res. 2010 Jun 18;
Authors: Anthony N, Shanks J, Terebelo H
PMID: 20646761 [PubMed - as supplied by publisher]
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17-N-Allylamino-17-demethoxygeldanamycin induces a diverse response in human acute myelogenous cells.
Leuk Res. 2010 Jun 18;
Authors: Napper JM, Sollars VE
The goal of this study was to ascertain the specific effects of 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) treatment in human acute myelogenous leukemia (AML). Four human leukemia cell lines were treated with varying doses of 17-AAG followed by analysis of toxicity, apoptosis, proliferation, and cell cycle. Cell cycle analysis revealed that the cells accumulate in G2/M phase within 96h of treatment, although the effect was not equivalent among the cell lines. p21, p53 expression and MDR1 activity were among the possible mechanisms uncovered for the differing responses. Exploiting these differences may allow for more effective combinatory treatments in patients with AML.
PMID: 20646760 [PubMed - as supplied by publisher]
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Posted by rob on July 21, 2010 under Uncategorized |
Erythroid Induction of Chronic Myelogenous Leukemia K562 Cells Following Treatment with a Photoproduct Derived from the UV-A Irradiation of 5-Methoxypsoralen.
ChemMedChem. 2010 Jul 19;
Authors: Salvador A, Dall’acqua S, Sardo MS, Caffieri S, Vedaldi D, Dall’acqua F, Borgatti M, Zuccato C, Bianchi N, Gambari R
Induction of terminal erythroid differentiation can be an efficient strategy to inhibit proliferation of chronic myelogenous leukemia cells. Psoralens, well-known photo-chemotherapeutic agents, were found to be efficient at inducing erythroid differentiation of K562 cells, an in vitro cell line isolated from the pleural effusion of a patient with chronic myelogenous leukemia in blast crisis. The effects of crude pre-irradiated solutions of 5-methoxypsoralen on erythroid differentiation of human leukemic K-562 cells were evaluated. The major photoproduct was characterized and analyzed, and it was found to induce erythroid differentiation of K562 cells and inhibit NF-kappaB/DNA interactions.
PMID: 20645383 [PubMed - as supplied by publisher]
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Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients.
Acta Pharmacol Sin. 2010 Jul 19;
Authors: Li QB, Chen C, Chen ZC, Wang HX, Wu YL, You Y, Zou P
AbstractAim:To investigate the pharmacokinetics of imatinib in Chinese chronic myelogenous leukemia (CML) patients.Methods:Fourty-six naïve Chinese CML patients treated with imatinib (400 and 600 mg daily, n=36 and 10, respectively) were recruited. The correlations of imatinib (400 mg) trough plasma concentrations (C(mins)) with the patients’ characteristics and responses were analyzed.Results:The overall mean (+/-SD, CV%) steady-state C(mins) for imatinib at 400 mg (n=36) and 600 mg (n=10) daily was 1325.61 ng/mL (+/-583.53 ng/mL; 44%) and 1550.90 ng/mL (+/-462.63 ng/mL; 30%), respectively, and no statistically significant differences were found between them (P=0.267). At 400 mg daily, female patients had significantly higher C(mins) than the male patients (P=0.048), and molecular responses were not correlated with imatinib C(mins), but they were correlated with time elapsed before imatinib therapy.Conclusion:The results suggest that Chinese CML patients have higher imatinib C(mins) than their Caucasian counterparts and that the optimal initial imatinib dose for them requires further investigation.
PMID: 20644548 [PubMed - as supplied by publisher]
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Researchers at Duke University Medical Center have identified a mechanism that could explain how patients move into the worst phase of chronic myelogenous leukemia (CML). Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML. This same molecular pathway may also be related to other aggressive leukemias, as well as solid tumors like glioblastoma (a severe form of brain cancer) and breast cancer… (Source: Health News from Medical News Today)
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Posted by rob on July 20, 2010 under Uncategorized |
Regulation of myeloid leukaemia by the cell-fate determinant Musashi.
Nature. 2010 Jul 18;
Authors: Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, Zhao C, Lagoo A, Gerrard G, Foroni L, Goldman J, Goh H, Kim SH, Kim DW, Chuah C, Oehler VG, Radich JP, Jordan CT, Reya T
Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.
PMID: 20639863 [PubMed - as supplied by publisher]
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Targeted therapy of chronic myeloid leukemia.
Biochem Pharmacol. 2010 Sep 1;80(5):584-91
Authors: Sullivan C, Peng C, Chen Y, Li D, Li S
Inhibition of BCR-ABL with kinase inhibitors has become a well-accepted strategy for targeted therapy of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML) and has been shown to be highly effective in controlling the disease. However, BCR-ABL kinase inhibitors do not efficiently kill leukemic stem cells (LSCs), indicating that this therapeutic strategy does not lead to a cure of CML. Development of curative therapies of CML require the identification of genes/pathways that play critical roles in survival and self-renewal of LSCs. Targeting of these key BCR-ABL downstream genes provides an opportunity to eradicate LSCs, as shown in our work that identifies the Alox5 gene as a key regulator of the function of CML LSCs. Immediate clinical trials are necessary to test the effectiveness of targeting a key BCR-ABL downstream gene in eradicating LSCs in CML patients. In this review, we will discuss current targeted therapies of CML using BCR-ABL kinase inhibitors, with a focus on the importance of developing a targeted therapy of CML through identification of target genes in CML LSCs.
PMID: 20470758 [PubMed - indexed for MEDLINE]
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Posted by rob on July 19, 2010 under Uncategorized |
(Duke University Medical Center) Researchers at Duke University Medical Center have identified a mechanism that could explain how patients move into the worst phase of chronic myelogenous leukemia (CML). Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML. (Source: EurekAlert! – Medicine and Health)
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Posted by rob on under Uncategorized |
Researchers have identified a mechanism that could explain how patients move into the worst phase of chronic myelogenous leukemia (CML). Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML. (Source: ScienceDaily Headlines)
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Posted by rob on July 16, 2010 under Uncategorized |
Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice.
Anticancer Drugs. 2010 Aug;21(7):695-703
Authors: Soo GW, Law JH, Kan E, Tan SY, Lim WY, Chay G, Bukhari NI, Segarra I
Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib’s protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution. Male ICR mice, 9-12 weeks old were given imatinib PO (50 mg/kg) alone or co-administered with primaquine (12.5 mg/kg), ketoconazole (50 mg/kg) or both, and imatinib concentration in the plasma, kidney, liver and brain was measured at prescheduled time points by HPLC. Noncompartmental pharmacokinetic parameters were estimated. Primaquine increased 1.6-fold plasma AUC(0)–> infinity, C(Max) decreased 24%, T(Max) halved and t(1/2) and mean residence time were longer. Ketoconazole increased plasma AUC(0)–>infinity 64% and doubled the C(Max), but this dose did not affect t(1/2) or mean residence time. When ketoconazole and primaquine were co-administered, imatinib AUC(0)–>infinity and C(Max) increased 32 and 35%, respectively. Ketoconazole did not change imatinib’s distribution efficiency in the liver and kidney, primaquine increased it two-fold and it was larger when both the drugs were co-administered with imatinib. Ketoconazole did not change brain penetration but primaquine increased it approximately three-fold. Ketoconazole and primaquine affect imatinib clearance, bioavailability and distribution pattern, which could improve the treatment of renal and brain tumors, but also increase toxicity. This would warrant hepatic and renal functions monitoring.
PMID: 20629201 [PubMed - in process]
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We describe a patient with an acute eruption of asymptomatic, erythematous, edematous, oval plaques studded with pinpoint, nonfollicular pustules on her torso and proximal extremities caused by sulfamethoxazole-trimethoprim (SMZ-TMP). This 40-year-old female had a history of chronic myelogenous leukemia unresponsive to etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab, and fludarabine (EPOCH-RF) therapy. She subsequently received a matched, related-donor peripheral blood stem cell transplant and donor lymphocyte infusion (DLI of TH2 cells). She presented on posttransplant day 15 (post-DLI day 1) with acute onset of the aforementioned eruption (). There were no vesicles, bullae, or mucosal lesions and experienced no fever, chills, lymphadenopathy, angioedema, or g…
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WebMD provides tips on coping with Chronic Myelogenous Leukemia symptoms and explains CML accelerated and blast phases. (Source: WebMD Health)
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Posted by rob on under Uncategorized |
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by p210-BCR-ABL–mediated transformation of hematopoietic stem cells (HSCs). Inhibition of the ABL kinase alone is not sufficient to eradicate leukemic stem cells (LSCs). We have previously shown that the deficiency of Rac2 GTPase signaling, but not Rac1, in p210-BCR-ABL–transduced hematopoietic cells prolonged survival of mice with MPD. Here we demonstrate that absence of Rac2 GTPase prolongs survival of HSC-initiated, inducible Scl/p210-BCR-ABL (Scl/p210) binary transgenic mice, it induces apoptosis, and, unlike in normal HSC and progenitor (HSC/P), impairs LSC and progenitor (LSC/P) proliferation in vivo. As a result, Rac2 deficiency causes functional exhaustion of the LSC pool in vivo. …
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ACS Chemical Biology, Volume 0, Issue 0, Articles ASAP (As Soon As Publishable). (Source: ACS Chemical Biology)
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Posted by rob on under Uncategorized |
We present a case of insufficient bilateral femoral subtrochanteric fractures in a patient who was treated with imatinib mesylate,
an anticancer drug, for 1 year after a diagnosis of chronic myelogenous leukemia (CML). A 60-year-old woman presented with
bilateral thigh pain for 6 months. A plain radiograph revealed bilateral progressive insufficient fractures on the subtrochanteric
areas of the femurs. MRI of the femurs revealed incomplete stress fractures and no evidence of bone metastasis on either femur.
Bone densitometry showed normal T-scores around the hip joint and spine. The patient had normal serum levels of calcium, vitamin
D derivatives, and thyroid hormones. Serum phosphate levels were decreased, and parathyroid hormone levels were increased.
Serum osteocalcin a…
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Posted by rob on under Uncategorized |
Authors: Yin L, Ahmad R, Kosugi M, Kawano T, Avigan D, Stone R, Kharbanda S, Kufe D
Chronic myelogenous leukemia (CML) is caused by expression of the Bcr-Abl fusion protein in hematopoietic stem cells. The MUC1-C oncoprotein is expressed in CML blasts and stabilizes Bcr-Abl. The present studies demonstrate that treatment of KU812 and K562 CML cells with GO-201, a cell-penetrating peptide inhibitor of MUC1-C oligomerization, downregulates Bcr-Abl expression and inhibits cell growth. In concert with decreases in Bcr-Abl levels, KU812 and K562 cells responded to GO-201 with induction of a differentiated myeloid phenotype as evidenced by increased expression of CD11b, CD11c and CD14. The results also show that the GO-201-treated cells undergo a late apoptotic/necrotic response, consistent …
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Posted by rob on July 5, 2010 under Uncategorized |
The Bcr-Abl kinase inhibitor imatinib is remarkably effective in chronic myelogenous leukemia (CML), although drug resistance is an emerging problem. Myeloid Src family kinases such as Hck and Lyn are often overexpressed in imatinib-resistant CML cells that lack Bcr-Abl mutations. Here we tested whether Hck overexpression is sufficient to induce imatinib resistance using both wild-type Hck and a mutant (Hck-T338A) that is uniquely sensitive to the pyrazolo-pyrimidine inhibitor, NaPP1. Expression of either kinase in K562 CML cells caused resistance to imatinib-induced apoptosis and inhibition of soft-agar colony formation. Treatment with NaPP1 restored sensitivity to imatinib in cells expressing T338A but not wild-type Hck, demonstrating that resistance requires Hck kinase activity. NaPP1 a…
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Posted by rob on July 3, 2010 under Uncategorized |
Uncommon BCR-ABL kinase domain mutations in kinase inhibitor-resistant chronic myelogenous leukemia and Ph+ acute lymphoblastic leukemia show high rates of regression, suggesting weak selective effects.
Blood. 2010 Jul 1;115(26):5428-5429
Authors: Jones D, Chen SS, Jabbour E, Rios MB, Kantarjian H, Cortes J
PMID: 20595523 [PubMed - as supplied by publisher]
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