Posted by rob on November 28, 2009 under Uncategorized | 
Acute myelogenous leukemia and acute leukemic appendicitis: A case report.
World J Gastroenterol. 2009 Nov 28;15(44):5624-5625
Authors: Hsiao PJ, Kuo SM, Chen JH, Lin HF, Chu PL, Lin SH, Ho CL
Acute myelogenous leukemia (AML) can involve the gastrointestinal tract but rarely involves the appendix. We report a male patient who had 1 year partial remission from AML and who presented with apparent acute appendicitis as the initial manifestation of leukemia relapse. Pathological findings of the appendix revealed transmural infiltrates of myeloblasts, which indicated a diagnosis of leukemia. Unfortunately, the patient died from progression of the disease on the 19th d after admission. Although leukemic cell infiltration of the appendix is uncommon, patients with leukemia relapse can present with symptoms mimicking acute appendicitis.
PMID: 19938205 [PubMed - as supplied by publisher]
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Intracardiac Chloroma.
J Pediatr Hematol Oncol. 2009 Nov 20;
Authors: Mignano JE, Chan MD, Rosenwald IB, Kimmelstiel CD, Wolfe LC
Chloromas are not frequently seen in patients with acute myelogenous leukemia and chloromas involving cardiac structures have only been rarely reported in the literature. We report a complete radiographic response to low-dose fractionated radiotherapy in a patient with an intracardiac chloroma.
PMID: 19935434 [PubMed - as supplied by publisher]
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Imatinib Mesylate Induces Cisplatin Hypersensitivity in Bcr-Abl+ Cells by Differential Modulation of p53 Transcriptional and Proapoptotic Activity.
Cancer Res. 2009 Nov 24;
Authors: Skorta I, Oren M, Markwardt C, Gutekunst M, Aulitzky WE, van der Kuip H
Imatinib is highly effective in inducing remission in chronic myelogenous leukemia (CML). However, complete eradication of the malignant clone by imatinib is rare. We investigated the efficacy of combining imatinib with cisplatin. Inhibition of Bcr-Abl by imatinib induced a hypersensitive phenotype both in Bcr-Abl(+) cell lines and in CD34(+) cells from CML patients. Importantly, cisplatin sensitivity of leukemic cells harboring an inactive Bcr-Abl greatly exceeded that of Bcr-Abl(-) parental cells. The cisplatin response of Bcr-Abl(+) cells treated with imatinib was characterized by an impaired G(2)-M arrest and by rapid induction of mitochondrial cell death after the first passage through G(2). Imatinib abrogated ATM activation on cisplatin selectively in Bcr-Abl(+) cells. As a consequence, phosphorylation of p53 on Ser(15) and its activity as a transcription factor was significantly diminished. Furthermore, p53 accumulated predominantly in the cytoplasm in Bcr-Abl(+) cells treated with imatinib and cisplatin. Silencing of p53 significantly reduced sensitivity to cisplatin in imatinib-treated Bcr-Abl(+) cells, indicating that p53 retains its proapoptotic activity. Simultaneous downregulation of Bcl-x(L) was an additional requirement for cisplatin hypersensitivity, as p53-dependent cell death could be antagonized by exogenous Bcl-x(L). We conclude that imatinib sensitizes Bcr-Abl(+) cells to cisplatin by simultaneous inhibition of p53 transactivation, induction of p53 accumulation predominantly in the cytoplasm, and reduction of Bcl-x(L). [Cancer Res 2009;69(24):OF1-9].
PMID: 19934315 [PubMed - as supplied by publisher]
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Acute myelogenous leukemia cells with the MLL-ELL translocation convert morphologically and functionally into adherent myofibroblasts.
Biochem Biophys Res Commun. 2009 Nov 20;
Authors: Tashiro H, Mizutani-Noguchi M, Shirasaki R, Shirafuji N
Bone marrow-myofibroblasts, a major component of bone marrow-stroma, are reported to originate from hematopoietic stem cells. We show in this paper that non-adherent leukemia blasts can change into myofibroblasts. When myeloblasts from two cases of acute myelogenous leukemia with a fusion product comprising mixed lineage leukemia and RNA polymerase II elongation factor, were cultured long term, their morphology changed to that of myofibroblasts with similar molecular characteristics to the parental myeloblasts. The original leukemia blasts, when cultured on the leukemia blast-derived myofibroblasts, grew extensively. Leukemia blasts can create their own microenvironment for proliferation.
PMID: 19932689 [PubMed - as supplied by publisher]
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Issues of imatinib and pregnancy outcome.
J Natl Compr Canc Netw. 2009 Nov;7(10):1050-8
Authors: Apperley J
The introduction of tyrosine kinase inhibitors into clinical practice now offers most patients with chronic myelogenous leukemia lengthy remissions and the possibility of normal life expectancies. These improved survivals have resulted in the need to address issues relating to quality of life, including fertility and procreation. Treatment may require lifelong daily therapy with drugs that might inhibit proteins essential to gonadal function, implantation, and embryogenesis. Animal data suggest that imatinib at standard dosages is unlikely to impair fertility in either adult male or female animals. However, human data remain limited, particularly in children and adolescents. Children born to men who are actively taking imatinib at conception seem healthy, and current advice is not to discontinue treatment. In contrast, data are less encouraging for children born to women exposed to imatinib during pregnancy. Although numbers are small, a disturbing cluster of rare congenital malformations has prevented imatinib from being recommended safely, particularly during the period of organogenesis. Alternative strategies for managing pregnancy in chronic myelogenous leukemia include one or both of regular leukapheresis and interferon-alpha. Pregnancy in advanced-phase disease presents particular problems.
PMID: 19930974 [PubMed - in process]
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Evolving strategies in the treatment of MDS and AML.
Clin Adv Hematol Oncol. 2009 Aug;7(8):1-14; quiz 2 p following 14
Authors: Stone R, Sekeres M, Garcia-Manero G
Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by a hyperproliferative bone marrow, cellular dysplasia, and ineffective hematopoiesis. This heterogeneous malignancy is composed of several subtypes, the classification of which has evolved over several years. The treatment of MDS involves improving patient survival and quality of life while decreasing the likelihood of progression to acute myelogenous leukemia (AML). In addition to supportive care with transfusions and hematopoietic growth factors as well as stem cell transplantation, three chemotherapeutic agents have been approved to treat MDS–lenalidomide, azacitidine, and decitabine. In addition, multiple agents and novel combinations are currently in development to treat both MDS AML. Several clinical studies which have investigated these therapeutic approaches, as well as the incorporation of new tools used in the diagnosis of MDS, have been published since the 2008 American Society of Hematology (ASH) Annual Meeting and Exposition, and are discussed here. By becoming familiar with these studies, the physician will be better able to provide the optimal treatment for their patients, as well as become aware of novel therapeutic strategies to offer their patients in ongoing clinical trials.
PMID: 19927982 [PubMed - in process]
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Posted by rob on November 20, 2009 under Uncategorized |
Acadesine Kills Chronic Myelogenous Leukemia (CML) Cells through PKC-Dependent Induction of Autophagic Cell Death.
PLoS One. 2009;4(11):e7889
Authors: Robert G, Ben Sahra I, Puissant A, Colosetti P, Belhacene N, Gounon P, Hofman P, Bost F, Cassuto JP, Auberger P
CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.
PMID: 19924252 [PubMed - as supplied by publisher]
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Cathepsin B release after imatinib-mediated lysosomal membrane permeabilization triggers BCR-ABL cleavage and elimination of chronic myelogenous leukemia cells.
Leukemia. 2009 Nov 19;
Authors: Puissant A, Colosetti P, Robert G, Cassuto JP, Raynaud S, Auberger P
Imatinib is the leading compound to treat patients with chronic myelogenous leukemia (CML) but the exact mechanism of its anti-leukemic effect is incompletely elucidated. Through inhibition of BCR-ABL, Imatinib blocks several downstream pathways and induces apoptosis of BCR-ABL positive cells. In this study, we analyzed further the mode of action of Imatinib in different appropriate cellular models of CML either sensitive or resistant to Imatinib and in CD34+ cells from CML patients. Pharmacological or short hairpin RNA-mediated inhibition of BCR-ABL triggers lysosomal membrane permeabilization (LMP) that culminates in activation and redistribution of Cathepsin B (CB) into the cytoplasm of CML cells, in which it triggers directly BCR-ABL degradation. Pharmacological inhibition of CB by CA-074Me or small interfering RNA-mediated knock-down of CB partly protects K562 cells from Imatinib-induced cell death and CB overexpression sensitizes these cells to Imatinib killing. Strikingly, Imatinib-triggered LMP, CB activation and BCR-ABL cleavage in CD34+ cells from CML patients and inhibition of CB confers protection against cell death in clonogenic assays of CD34+ primary cells from CML patients. Hence, we describe an original pathway by which Imatinib participates to the elimination of CML cells through LMP and CB-mediated specific degradation of BCR-ABL.Leukemia advance online publication, 19 November 2009; doi:10.1038/leu.2009.233.
PMID: 19924144 [PubMed - as supplied by publisher]
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Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: A randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers.
Clin Ther. 2009 Oct;31(10):2224-2232
Authors: Parrillo-Campiglia S, Ercoli MC, Umpierrez O, Rodríguez P, Márquez S, Guarneri C, Estevez-Parrillo FT, Laurenz M, Estevez-Carrizo FE
Background: Imatinib is a tyrosine kinase inhibitor that has been established as a highly effective therapy for chronic myelogenous leukemia and gastrointestinal stromal tumors. A new generic, once-daily 400-mg tablet of imatinib has been developed by a pharmaceutical company in Argentina, where the regulatory standard for marketing authorization of an imatinib generic is in vitro dissolution testing. Objective: The aim of this study was to assess the bioequivalence of a new generic film-coated test tablet formulation versus a film-coated reference tablet formulation of imatinib 400 mg. The local manufacturer seeks to validate the in vitro performance of this new formulation with a bioequivalence study. Methods: A randomized, open-label, single-dose, fasting, 2-period, 2-sequence crossover design with a 2-week washout period was used in this study. The study population consisted of healthy male South American (Uruguayan) volunteers, who were assigned in a 1:1 ratio to a randomized sequence (test-reference or reference-test). In each period, the test or reference formulation was administered after an overnight fast. During the 72-hour follow-up period, participants were monitored for vital signs and symptoms. Blood samples were collected at 15 time points, including baseline, until 72 hours. Physical examination and laboratory tests (blood, urine) were repeated 1 week after study completion. A noncompartmental model was used to determine the pharmacokinetic parameters of imatinib. The 90% CIs of the test/reference ratios for AUC(0-infinity) and C(max) were determined; the test and reference formulations were considered bioequivalent if the 90% CIs were between 0.80 and 1.25. Adverse events were assessed by a nurse who administered a questionnaire while the healthy volunteers were admitted in the unit. Results: The bioequivalence study was conducted in 30 Uruguayan male volunteers. Demographic characteristics (mean [SD]) included age, 27.8 (6.5) years; weight, 71.2 (9.8) kg; height, 1.71 (0.09) m; and body mass index, 24.3 (3.0) kg/m2. The mean (SD) of AUC(0-infinity) was 38,179 (15,504) ng/mL . h(-1) for the test formulation and 40,554 (17,027) ng/mL . h(-1) for the reference formulation. The mean of Cmax for the test formulation was 2472 (933) ng/mL, and the mean Tmax was 3.28 (0.93) hours. The mean of Cmax for the reference formulation was 2566 (963) ng/mL, and the mean T(max) was 3.63 (1.20) hours. The point estimates (90% CIs) for the test/reference ratios of the log-transformed AUC- and C(max) mean values were 0.95 (0.87-1.03) and 0.97 (0.89-1.05), respectively, which met the regulatory criteria for bioequiv-alence. Thirty-four mild to moderate adverse events were reported (13 with the test formulation and 21 with the reference formulation), and no serious or unexpected adverse events were observed during the study. The adverse events included 16 cases of headache, 13 cases of nausea, 4 cases of vomiting, and 1 episode of diarrhea. Conclusions: The results of this study suggest that the test formulation of imatinib met the regulatory criteria for bioequivalence to the reference formulation in these healthy fasting male volunteers. Both formulations were generally well tolerated and appeared to have a similar adverse-event profile.
PMID: 19922893 [PubMed - as supplied by publisher]
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Extended kinase profile and properties of the protein kinase inhibitor Nilotinib.
Biochim Biophys Acta. 2009 Nov 13;
Authors: Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, Mestan J, Trappe J, Wartmann M, Fabbro D
As a drug used to treat imatinib-resistant and -intolerant, chronic and advanced phase chronic myelogenous leukaemia, nilotinib is well characterised as a potent inhibitor of the Abl tyrosine kinase activity of wild-type and imatinib-resistant mutant forms of BCR-Abl. Here we review the profile of nilotinib as a protein kinase inhibitor. Although an ATP-competitive inhibitor of Abl, nilotinib binds to a catalytically inactive conformation (DFG-out) of the activation-loop. As a consequence of this, nilotinib exhibits time-dependent inhibition of Abl kinase in enzymatic assays, which can be extrapolated to other targets to explain differences between biochemical activity and cellular assays. Although these differences confound assessment of kinase selectivity, as assessed using a combination of protein binding and transphosphorylation assays, together with cellular autophosporylation and proliferation assays, well established kinase targets of nilotinib in rank order of inhibitory potency are DDR-1 > DDR-2 > BCR-Abl (Abl) > PDGFRalpha/beta > KIT > CSF-1R. In addition nilotinib has now been found to bind to both MAPK11 (p38beta) and MAPK12 (p38alpha), as well as with very high affinity to ZAK kinase. Although neither enzymatic nor cellular data are yet available to substantiate the drug as an inhibitor of ZAK phosphorylation, modeling predicts that it binds in an ATP-competitive fashion.
PMID: 19922818 [PubMed - as supplied by publisher]
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PRIMARY HUMAN ACUTE MYELOGENOUS LEUKEMIA CELLS RELEASE MATRIX METALLOPROTEASES AND THEIR INHIBITORS: RELEASE PROFILE AND PHARMACOLOGICAL MODULATION.
Eur J Haematol. 2009 Nov 17;
Authors: Reikvam H, Hatfield KJ, Oyan AM, Kalland KH, Kittang AO, Bruserud O
Abstract Objectives: Angiogenesis seems important both for leukemogenesis and chemosensitivity in acute myelogenous leukemia (AML). Angiogenesis is regulated by the balance between pro- and antiangiogenic cytokines, which also indicates an important role of matrix metalloproteases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteases (TIMPs), in angiogenesis. We investigated the constitutive release of MMPs and TIMPs for a large group of consecutive AML patients. Methods: AML cells were cultured in vitro either alone or together with microvascular endothelial cells and levels of MMPs and TIMPs were determined in culture supernatants. Results: AML cells showed constitutive release of several MMPs and TIMPs. For all patients detectable MMP-10 release was observed, and most patients showed detectable release of at least one additional MMP, usually MMP-9 or MMP-2. A significant correlation was found between MMP-9 and TIMP-1 release and the release of several CCL and CXCL chemokines. MMP-9 release was higher for AML cells with monocytic differentiation corresponding to the FAB-subtype M4/M5 AML; it was mainly released in its inactive form, but endogenous active MMP-9 could be detected even in the presence of the constitutively released TIMP-1/2. Endothelial cells released relatively high levels of MMP-10, and these levels were further increased by coculture with AML cells. Patients achieving complete hematological remission after only one induction cycle showed relatively low constitutive MMP-2 release. Conclusion: We conclude that primary human AML cells show constitutive release of both MMPs and TIMPs, and this release may be important for leukemogenesis and possibly also for chemosensitivity.
PMID: 19922462 [PubMed - as supplied by publisher]
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Posted by rob on November 19, 2009 under Uncategorized |
Authors: Lamm SH, Engel A, Joshi KP, Byrd DM, 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) o…
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Posted by rob on November 18, 2009 under Uncategorized |
Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity.
Blood. 2009 Oct 22;114(17):3684-92
Authors: Stumpf AN, van der Meijden ED, van Bergen CA, Willemze R, Falkenburg JH, Griffioen M
Potent graft-versus-leukemia (GVL) effects can be mediated by donor-derived T cells recognizing minor histocompatibility antigens (mHags) in patients treated with donor lymphocyte infusion (DLI) for relapsed hematologic malignancies after HLA-matched allogeneic stem cell transplantation (alloSCT). Donor-derived T cells, however, may not only induce GVL, but also mediate detrimental graft-versus-host disease (GVHD). Because HLA-class II is under noninflammatory conditions predominantly expressed on hematopoietic cells, CD4+ T cells administered late after alloSCT may selectively confer GVL without GVHD. Although a broad range of different HLA-class I-restricted mHags have been identified, the first 2 autosomal HLA-class II-restricted mHags have only recently been characterized. By screening a recombinant bacteria cDNA expression library, we identified 4 new HLA-class II-restricted mHags recognized by CD4+ T cells induced in a patient with relapsed chronic myeloid leukemia who achieved long-term complete remission and experienced only mild GVHD of the skin after DLI. All CD4+ T cells were capable of recognizing the mHags presented by HLA-DR surface molecules on primary hematopoietic cells, but not on skin-derived (cytokine-treated) fibroblasts. The selective recognition of hematopoietic cells as well as the balanced population frequencies and common HLA-DR restriction elements make the novel mHags possible targets for development of immunotherapeutic strategies.
PMID: 19706888 [PubMed - indexed for MEDLINE]
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Priapism as the first manifestation of chronic myeloid leukemia.
Ann Saudi Med. 2009 Sep-Oct;29(5):412
Authors: Tazi I
PMID: 19700904 [PubMed - indexed for MEDLINE]
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Spontaneous spinal epidural hematoma as the initial presentation of leukemia.
Eur Spine J. 2009 Jul;18 Suppl 2:220-3
Authors: Nojiri H, Kim S, Tsuji T, Uta S
We present a case of a 55-year-old male with progressive neurological deficits that appeared dramatically. MRI detected a spinal epidural hematoma at the cervicothoracic junction and blood tests showed leukocytosis, mild anemia, and thrombocytosis. Spontaneous spinal epidural hematoma (SSEH) as the initial presentation of leukemia was diagnosed. Urgent posterior decompression was performed after 28 h from acute onset of backache, and the patient experienced remarkable improvement in neurological findings.
PMID: 19127372 [PubMed - indexed for MEDLINE]
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Posted by rob on November 14, 2009 under Uncategorized |
Title: Chronic Myelogenous Leukemia (CML)Category: Doctor’s ViewsCreated: 11/11/2009 2:29:00 PMLast Editorial Review: 11/11/2009 2:29:15 PM (Source: MedicineNet Cancer General)
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Title: Chronic Myelogenous Leukemia (CML)Category: Doctor’s ViewsCreated: 11/11/2009 2:29:00 PMLast Editorial Review: 11/11/2009 2:29:15 PM (Source: MedicineNet Crohn’s Disease General)
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Title: Chronic Myelogenous Leukemia (CML)Category: Doctor’s ViewsCreated: 11/11/2009 2:29:00 PMLast Editorial Review: 11/11/2009 2:29:15 PM (Source: MedicineNet Senior Health General)
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Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib.
PLoS Comput Biol. 2009 Sep;5(9):e1000503
Authors: Foo J, Drummond MW, Clarkson B, Holyoake T, Michor F
Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic.
PMID: 19749982 [PubMed - indexed for MEDLINE]
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Posted by rob on November 10, 2009 under Uncategorized |
Authors: Huang M, Hu Z, Chang W, Ou D, Zhou J, Zhang Y
The activation of ABL tyrosine kinase in BCR/ABL-positive chronic myelogenous leukemia (CML) leads to a diversity of biological changes related to the pathogenesis of the disease. In CML patients, we determined the expression of growth factor independence-1 (Gfi1), a transcription repressor with weak oncogenic activity. Our data demonstrated that the Gfi1 mRNA level in both the mononuclear cells and purified CD34(+) cells from CML were significantly higher as measured by quantitative real-time PCR. Using flow cytometry and Western blot, we also showed that the Gfi1 protein content was increased in CML CD34(+) cells. The expression of Gfi1 was correlated with BCR/ABL significantly. Gfi1 may be implicated in the pathogenesis of CML a…
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