Posted by rob on August 22, 2010 under Uncategorized | 
Co-expression of HoxA9 and bcr-abl genes in chronic myeloid leukemia.
Leuk Lymphoma. 2010 May;51(5):892-6
Authors: Tedeschi FA, Cardozo MA, Valentini R, Zalazar FE
We have analyzed the co-expression of the bcr-abl and HoxA9 genes in the follow-up of patients with chronic myeloid leukemia (CML). In the present work we measured the HoxA9 and bcr-abl gene expression in sequential samples. In all patients, bcr-abl and HoxA9 were expressed at detectable levels in every sample. When the results were expressed in relation to abl, two different situations were found: (a) patients clinically stable at second sampling, with low relative risk at diagnosis (low Sokal’s score), did not show significant differences in both bcr-abl and HoxA9 levels in the sequential samples analyzed, and (b) patients with poor prognosis (showing intermediate or high Sokal’s score at diagnosis) had increased expression of bcr-abl as well as HoxA9 genes (p < 0.05). Since HoxA9 gene expression remains at relatively constant levels throughout adult life, our results could reflect actual changes in the expression rate of this gene associated with bcr-abl during the progression of CML.
PMID: 20141430 [PubMed - indexed for MEDLINE]
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Posted by rob on August 19, 2010 under Uncategorized |
A Non-ATP-Competitive Dual Inhibitor of JAK2 and BCR-ABL Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition.
Genes Cancer. 2010 May 1;1(4):331-345
Authors: Jatiani SS, Cosenza SC, Reddy MV, Ha JH, Baker SJ, Samanta AK, Olnes MJ, Pfannes L, Sloand EM, Arlinghaus RB, Reddy EP
Here we report the discovery of ON044580, an alpha-benzoyl styryl benzyl sulfide that possesses potent inhibitory activity against two unrelated kinases, JAK2 and BCR-ABL, and exhibits cytotoxicity to human tumor cells derived from chronic myelogenous leukemia (CML) and myelodysplasia (MDS) patients or cells harboring a mutant JAK2 kinase. This novel spectrum of activity is explained by the non-ATP-competitive inhibition of JAK2 and BCR-ABL kinases. ON044580 inhibits mutant JAK2 kinase and the proliferation of JAK2(V617F)-positive leukemic cells and blocks the IL-3-mediated phosphorylation of JAK2 and STAT5. Interestingly, this compound also directly inhibits the kinase activity of both wild-type and imatinib-resistant (T315I) forms of the BCR-ABL kinase. Finally, ON044580 effectively induces apoptosis of imatinib-resistant CML patient cells. The apparently unrelated JAK2 and BCR-ABL kinases share a common substrate, STAT5, and such substrate competitive inhibitors represent an alternative therapeutic strategy for development of new inhibitors. The novel mechanism of kinase inhibition exhibited by ON044580 renders it effective against mutant forms of kinases such as the BCR-ABL(T315I) and JAK2(V617F). Importantly, ON044580 selectively reduces the number of aneuploid cells in primary bone marrow samples from monosomy 7 MDS patients, suggesting another regulatory cascade amenable to this agent in these aberrant cells. Data presented suggest that this compound could have multiple therapeutic applications including monosomy 7 MDS, imatinib-resistant CML, and myeloproliferative neoplasms that develop resistance to ATP-competitive agents.
PMID: 20717479 [PubMed - as supplied by publisher]
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T-regulatory cell response in psoriasis and changes with imatinib therapy.
Clin Exp Dermatol. 2009 Dec;34(8):e1022
Authors: Thachil J
PMID: 20055827 [PubMed - indexed for MEDLINE]
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Authors: Puissant A, Robert G, Auberger P
Macroautophagy, referred hereafter to as autophagy is an evolutionary conserved catabolic process for the degradation and recycling of macromolecules, bulk cytoplasm and dammaged organelles. Autophagy is activated under stress conditions induced by nutrient deprivation, hypoxia and drug treatments. Morphologically, autophagic cells are characterized by the accumulation of double membrane cytoplasmic vesicules called autophagosomes that surrounds cytoplasmic proteins and/or organelles. Autophagosomes next fuse with lysosomes to generate autolysosomes, the structures in which the retained constituents are digested before recycling into the cytoplasm. In this context, autophagy promotes cell survival under adverse conditions. In contrast, under ce…
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Posted by rob on August 17, 2010 under Uncategorized |
Hematopoietic stem cell emergence in the conceptus and the role of Runx1.
Int J Dev Biol. 2010;54(6-7):1151-63
Authors: Swiers G, De Bruijn M, Speck NA
Hematopoietic stem cells (HSCs) are functionally defined as cells that upon transplantation into irradiated or otherwise immunocompromised adult organisms provide long-term reconstitution of the entire hematopoietic system. They emerge in the vertebrate conceptus around midgestation. Genetic studies have identified a number of transcription factors and signaling molecules that act at the onset of hematopoiesis, and have begun to delineate the molecular mechanisms underlying the formation of HSCs. One molecule that has been a particularly useful marker of this developmental event in multiple species is Runx1 (also known as AML1, Pebp2a). Runx1 is a sequence-specific DNA-binding protein, that along with its homologues Runx2 and Runx3 and their shared non-DNA binding subunit CBFb, constitute a small family of transcription factors called core-binding factors (CBFs). Runx1 is famous for its role in HSC emergence, and notorious for its involvement in leukemia, as chromosomal rearrangements and inactivating mutations in the human RUNX1 gene are some of the most common events in de novo and therapy-related acute myelogenous leukemia, myelodysplastic syndrome and acute lymphocytic leukemia. Here we will review the role of Runx1 in HSC emergence in the mouse conceptus and describe some of the genetic pathways that operate upstream and downstream of this gene. Where relevant, we will include data obtained from other species and embryonic stem (ES) cell differentiation cultures.
PMID: 20711992 [PubMed - in process]
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“Real-life” results of front-line treatment with Imatinib in older patients (>/=65 years) with newly diagnosed chronic myelogenous leukemia.
Leuk Res. 2010 Aug 12;
Authors: Latagliata R, Breccia M, Carmosino I, Cannella L, De Cuia R, Diverio D, Frustaci A, Loglisci G, Mancini M, Santopietro M, Stefanizzi C, Volpicelli P, Vozella F, Alimena G
The age role was evaluated in 117 consecutive patients with newly diagnosed CML at our Institution treated with front-line Imatinib from 9/02 to 3/08. Forty patients (34.1%) aged >/=65 years and 77 (65.9%) <65 years. Thirty-four older patients (85%) had at least 1 comorbidity versus 39 younger patients (50.6%) (p<0.001). Complete cytogenetic response (CCyR) was achieved in 34/40 older patients (85%) as compared to 69/77 younger patients (89.6%), without statistically significant differences. Severe (grades 3-4 WHO) hematological and extra-hematological toxicities were more common in older patients (p=0.02 and p=0.017, respectively). Rates of permanent Imatinib discontinuation and dose reduction to 300mg or less were significantly higher in older patients (p=0.009 and p=0.001, respectively). In conclusion, Imatinib in older patients with newly diagnosed CML seems to have the same efficacy as in younger patients, but tends to be more toxic, leading to higher rates of discontinuation and dose reduction. To overcome this problem, future trials concerning best dosage in this subset of patients could be useful.
PMID: 20708799 [PubMed - as supplied by publisher]
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Validating cancer drug targets through chemical genetics.
Biochim Biophys Acta. 2010 Aug 11;
Authors: Burkard ME, Jallepalli PV
Targeted therapies for cancer promise to revolutionize treatment by specifically inactivating pathways needed for the growth of tumor cells. The most prominent example of such therapy is imatinib (Gleevec), which targets the Bcr-Abl kinase and provides an effective low-toxicity treatment for chronic myelogenous leukemia. This success has spawned myriad efforts to develop similarly targeted drugs for other cancers. Unfortunately, the high expectations of these efforts have not yet been realized, likely due to the genetic diversity among and within tumors, as well as the complex and largely unpredictable interactions of drug-like compounds with innumerable targets that affect cellular and organismal metabolism. While improvements in sequencing technologies are beginning to address the first problem, solving the second problem requires methods for linking specific features of the cancer genome to their optimally targeted therapies. One approach, referred to as chemical genetics, accomplishes this by genetic control of chemical susceptibility. Chemical genetics is a crucial tool for the rational development of cancer drugs.
PMID: 20708654 [PubMed - as supplied by publisher]
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Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases.
Ann Hematol. 2010 Sep;89(9):861-71
Authors: Han L, Schuringa JJ, Mulder A, Vellenga E
A number of signaling pathways might be frequently disrupted in acute myeloid leukemia (AML). We questioned whether the dual SRC/ABL kinase inhibitor dasatinib can affect AML cells and whether differences can be observed with normal CD34(+) cells. First, we demonstrated that normal cord blood (CB) CD34(+) cells were unaffected by dasatinib at a low concentration (0.5 nM) in the long-term culture on MS5 stromal cells. No changes were observed in proliferation, differentiation, and colony formation. In a subset of AML cases (3/15), a distinct reduction in cell proliferation was observed, ranging from 48% to 91% inhibition at 0.5 nM of dasatinib, in particular, those characterized by BCR-ABL or KIT mutations. Moreover, the inhibitory effects of dasatinib were cytokine specific. Stem cell factor-mediated proliferation was significantly impaired, associated with a reduced phosphorylation of ERK1/2 and STAT5, whereas no effect was observed on interleukin-3 and thrombopoietin-mediated signaling despite SRC activation. In conclusion, this study demonstrates that dasatinib is a potential inhibitor in a subgroup of AML, especially those that express BCR-ABL or KIT mutations.
PMID: 20387067 [PubMed - indexed for MEDLINE]
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Posted by rob on August 16, 2010 under Uncategorized |
Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) exert their anti-proliferative activity by interfering with Akt-mTOR signaling and bax:bcl-2 ratio modulation in cells from chronic myeloid leukemic patients.
Cancer Sci. 2010 Apr;101(4):991-1000
Authors: Di Stefano C, Marfe G, Trawinska MM, Sinibaldi-Salimei P, Silvestri R, Amadori S, Abruzzese E
In our study we found that pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) mediated apoptosis in primary leukemia cells from 27 chronic myelogenous leukemia (CML) patients at onset through the activation of the caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP). The bax:bcl-2 ratio was increased as a consequence of down-regulation of bcl-2 and up-regulation of bax proteins in response to treatment with PBTDs. In addition, PBTDs were able to induce cell death in primary leukemia cells derived from 23 CML-chemoresistant patients. Furthermore, the effects of PBTDs on the Akt-mTOR (mammalian target of rapamycin) pathway were determined by Western blot. PBTDs possessed inhibitory activity against mTOR and also impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. The results presented in this study demonstrate that we have identified the PBTDs as restoring the apoptotic pathways both in primary leukemia cells derived from CML patients at onset and in primary leukemia cells derived from CML-chemoresistant patients, thus showing their ability to undergo apoptosis. These compounds constitute a promising therapeutic approach for patients with leukemia. They provide the basis for new strategies for an additional anticancer drug in leukemia therapies, especially when conventional ones fail. (Cancer Sci 2010; 101: 991-1000).
PMID: 20704577 [PubMed - in process]
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Uncommon case of chronic myeloid leukemia with multiple myeloma.
Int J Hematol. 2010 May;91(4):699-704
Authors: Ide M, Kuwahara N, Matsuishi E, Kimura S, Gondo H
We describe a 72-year-old woman who was diagnosed with asymptomatic multiple myeloma (MM) while being treated for Philadelphia (Ph)-positive chronic myeloid leukemia (CML) with imatinib mesylate (400 mg/day). The diagnosis of CML was based on the presence of the Ph chromosome and chimeric BCR-ABL messenger RNA. Three months after starting imatinib mesylate treatment, the patient achieved a complete cytogenetic response. However, bone marrow analysis at that time demonstrated plasmacytosis, and paraprotein (IgG, kappa-type) was also detected. Hypercalcemia, renal failure, anemia, and bone lesions were not observed, which suggested that asymptomatic MM had developed. The coexistence of CML and MM is an extremely uncommon event that has only been reported in 12 cases. We discuss the relationship between CML and MM.
PMID: 20352382 [PubMed - indexed for MEDLINE]
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Skin fragility and blistering with imatinib mesylate.
J Eur Acad Dermatol Venereol. 2010 Apr;24(4):496-8
Authors: Verma SM, Murphy G
PMID: 19925597 [PubMed - indexed for MEDLINE]
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Posted by rob on August 13, 2010 under Uncategorized |
Targeting autophagy to fight hematopoietic malignancies.
Cell Cycle. 2010 Sep 15;9(17)
Authors: Puissant A, Robert G, Auberger P
Macroautophagy, referred hereafter to as autophagy is an evolutionary conserved catabolic process for the degradation and recycling of macromolecules, bulk cytoplasm and dammaged organelles. Autophagy is activated under stress conditions induced by nutrient deprivation, hypoxia and drug treatments. Morphologically, autophagic cells are characterized by the accumulation of double membrane cytoplasmic vesicules called autophagosomes that surrounds cytoplasmic proteins and/or organelles. Autophagosomes next fuse with lysosomes to generate autolysosomes, the structures in which the retained constituents are digested before recycling into the cytoplasm. In this context, autophagy promotes cell survival under adverse conditions. In contrast, under certain circumstances autophagic cells may engage a specific mode of cell death called type II cell death or autophagic cell death (ACD). Considering the strategic positionnement of this process at the crossroads of cell death and survival, it is not surprising that defects in autophagy have been linked to a plethora of human diseases, including hematopoietic malignancies. Finally, autophagy induction is repressed by the mammalian target of rapamycin complex 1 (mTORC1) and favored by the adenosine-monophosphate activated-protein kinase (AMPK). In the present review, we focus on the functions of autophagy in normal and malignant hematopoiesis and discuss the opportunity to target the AMPK/mTOR pathways as a new therapeutic strategy to fight hematopoietic malignancies with a special emphasis on Chronic Myelogenous Leukemia (CML).
PMID: 20703092 [PubMed - as supplied by publisher]
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Posted by rob on under Uncategorized |
This study suggests that the Flu/Bu/TBI 400 cGy or Flu/Bu/TBI 400 cGy/ATG-based conditioning regimens maybe a feasible therapeutic approach for AML with old age and/or co-morbidities.
PMID: 20694843 [PubMed - as supplied by publisher] (Source: International Journal of Hematology)
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Posted by rob on August 12, 2010 under Uncategorized |
Insulin Receptor A and IGF-IR in AML -Response.
Cancer Res. 2010 Aug 10;
Authors: Wahner Hendrickson AE, Haluska P, Erlichman C, Gottardis M, Carboni JE, Karp JE, Kaufmann SH
We applaud Chapuis and coworkers for recently showing an autocrine loop involving insulin-like growth factor I (IGF-I) and its receptor (IGF-IR) in acute myelogenous leukemia (AML). Although these studies identify IGF-IR as a potential therapeutic target, they do not address the contribution of insulin receptor isoform A (InsR-A) to AML. Doepfner and colleagues have reported that InsR is overexpressed on 85% of primary AML samples (1), and we have shown that this is exclusively InsR-A. Importantly, InsR seems to contribute to AML cell proliferation independent of IGF-IR, as evidenced by the equal antiproliferative effects of selective InsR and IGF-IR siRNAs in U937 cells (1). As we and others (1) have shown, certain AML lines and clinical samples also express IGF2, a high-affinity ligand for both IGF-IR and InsR-A. Collectively, these results raise the possibility that InsR-initiated signaling might contribute to the resistance observed by Chapuis in 30% of AML specimens treated with anti-IGF-IR antibody. Moreover, even AML specimens that respond to IGF-IR antibodies in vitro might need to be considered in light of emerging evidence that upregulated InsR-A signaling renders cells resistant to anti-IGF-IR therapy in vivo (2, 3). These observations provide a strong rationale for targeting both IGF-IR and InsR. Chapuis and colleagues question whether signaling by IGF-IR or InsR ontributes to extracellular signal-regulated kinase (ERK) activation in AML. The data in our article show that IGF-I and Ins induce ERK phosphorylation when added to serum-depleted cells, but ERK remains phosphorylated in serum-treated cells exposed to BMS-536924 concentrations that inhibit IGF-IR/InsR activity and Akt phosphorylation. Thus, IGF-IR and InsR can contribute to ERK activation, but other signaling molecules clearly contribute as well. Chapuis and colleagues also suggest that BMS-536924-induced apoptosis might represent an off-target effect. Interestingly, the structurally distinct IGF-IR (and at higher concentrations InsR) inhibitor NVP-AEW541 also induces apoptosis in AML cell lines and clinical samples (1). Further studies are required to determine whether this reflects inhibition of IGF-IR and InsR or another target. Finally, Chapuis and colleagues speculate that IGF-IR/InsR inhibitors might induce more hyperglycemia than anti-IGF-IR antibodies. Contrary to this view, emerging clinical data show that hyperglycemia, the most common adverse event with the anti-IGF-IR antibody figitumumab (4), might actually be less problematic with IGF-IR/InsR kinase inhibitors given on a daily basis (5), perhaps due to their shorter serum half-lives. Thus, studies that assess both the efficacy and the toxicity of the two approaches in AML are awaited with interest. Disclosure of Potential Conflicts of Interest M. Gottardis and J.M. Carboni are employed by Bristol-Myers Squibb. P. Haluska has received research funding from and has served as a consultant for Bristol-Myers Squibb.
PMID: 20699368 [PubMed - as supplied by publisher]
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Insulin Receptor A and IGF-1R in AML – Letter.
Cancer Res. 2010 Aug 10;
Authors: Chapuis N, Lacombe C, Tamburini J, Bouscary D, Mayeux P
In support of the recent article by Wahner Hendrickson and colleagues (1), we wish to share our data on the implication of insulin-like growth factor-1(IGF-1)/IGF-1 receptor (IGF-1R) signaling in acute myelogenous leukemia (AML). Indeed, we recently reported that a constitutively activated IGF-1R is expressed in AML cells (2). The authors hypothesize that an autocrine/paracrine stimulation of IGF-1R or insulin receptor isoform A (IR-A) could explain the overactivation of phosphoinositide-3-kinase (PI3K)/Akt and ERK/MAPK signaling in AML cells, thereby providing a rationale for dual IGF-1R/IR-A inhibition. In fact, in our previous works, we clearly established the existence of an IGF-1 autocrine production (3) and its critical role in PI3K deregulation in a cohort of 40 primary AML samples (2). Our results suggest that this PI3K/Akt activation is mediated through the IGF-1R rather than the IR-A, as specific inhibition of IGF-1R signaling with a neutralizing anti-IGF-1R antibody (alphaIR3) markedly inhibits the Akt constitutive phosphorylation in 70% of AML samples with deregulated PI3K activity (2). Interestingly, according to Wahner Hendrickson’s data, IR-A signaling might potentially be implicated in PI3K deregulation in alphaIR3-resistant patients. Conversely, we assume that deregulation of ERK1/2 does not occur downstream of the IGF-1R, as alphaIR3 does not decrease ERK1/2 phosphorylation (2). The implication of IR-A in ERK1/2 constitutive activity is unlikely because, in our experiments, exogenous IGF-1 stimulation, which also triggers IR-A activation (1), never led to an increase of ERK1/2 phosphorylation (2). Finally, a constitutive ERK1/2 phosphorylation is detectable even in samples without constitutive PI3K activity, thereby suggesting that both deregulations proceed from different mechanisms (2). Altogether, Wahner Hendrickson and colleagues suggest that targeting IGF-1R and IR could have a significant therapeutic value in AML. Accordingly, we found that alphaIR3 inhibits the proliferation of primary AML cells but does not induce apoptosis (2). Interestingly, dual IGF-1R and IR-A inhibition may have stronger activity in AML, as suggested by the induction of apoptosis by BMS-536924 (1), thereby underlying a potential contribution of IR-A signaling to the survival of AML cells. However, it cannot be ruled out that other kinases involved in cell survival are also inhibited by BMS-536924, as the specificity of tyrosine kinase inhibitors is generally uncertain. Furthermore, generalized IR inhibition might induce more serious side effects than blocking IGF-1R alone, especially towards the glucose metabolism. Indeed, insulin resistance and compensatory hyperinsulinemia have been reported in mice treated with BMS-554417, another dual IGF-1R/IR inhibitor (4). Finally, how to introduce these new strategies in the arsenal of AML therapy remains an ongoing challenge. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
PMID: 20699367 [PubMed - as supplied by publisher]
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[Therapeutic Drug Monitoring of Tyrosine-Kinase Inhibitors in the Treatment of Chronic Myelogenous Leukaemia: Interests and Limits.]
Therapie. 2010 5-6;65(3):213-218
Authors: Bouchet S, Royer B, Le Guellec C, Titier K
During the last decade, imatinib was current gold standard treatment of chronic myelogenous leukemia (CML), showing a great effectiveness. Thus, the Therapeutic Drug Monitoring (TDM), rarely applied in clinical oncology practice, did not appear necessary at the moment. However, the absence of response among patients and the metabolic profile of imatinib (involving the CYP3A4) suggested the existence of a great interindividual variability. During the last 4 years, studies about the pharmacokinetic/pharmacodynamic relationship have confirmed this variability and highlighted a relation between the trough concentrations of imatinib and the clinical response. An effectiveness threshold, close to 1000 ng/mL, seems to be correlated with better cytogenetic and molecular responses. Consequently, TDM could assist in investigation of the observance, the absence of response, the drug-drug interactions, but the proof of its utility requires complementary studies. In conclusion, the level of proof of imatinib TDM in LMC varies between levels << recommended >> and << potentially useful >>.
PMID: 20699073 [PubMed - as supplied by publisher]
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Posted by rob on August 11, 2010 under Uncategorized |
Characterization of a New Monoclonal Antibody Against PAX5/BASP in 1525 Paraffin-embedded Human and Animal Tissue Samples.
Appl Immunohistochem Mol Morphol. 2010 Aug 6;
Authors: Agostinelli C, Sabattini E, Gjørret JO, Righi S, Rossi M, Mancini M, Piccaluga PP, Bacci F, Marafioti T, Bettini G, Falini B, Pileri SA
INTRODUCTION: We describe the newly generated DAK-PAX5 monoclonal antibody raised against a fixation-resistant epitope of the human PAX5/BSAP molecule. MATERIALS AND METHODS: Following Western-blot, absorption, and chess-board titration tests, and optimization of antigen-retrieval and detection methods, DAK-Pax5 was used in parallel with a reference antibody (clone 24) on tissue micro-arrays (TMAs) constructed from normal human and animal tissues and from hematologic and nonhematologic human malignancies. Such TMAs were also tested with an anti-PAX2 antibody. RESULTS: DAK-Pax5 reacted with normal human and animal B-cells and with 460/473 B-cell non-Hodgkin lymphomas (B-NHLs). All plasmacytomas/plasmablastic tumors (n=13) and T/NK-cell neoplasms (n=264) turned out consistently negative as did acute myelogenous leukaemias (n=19) except 2 carrying t(8;21). Positivity was found in 6/6 and 155/169 lymphocyte predominant and classical HLs, respectively, although the staining intensity varied through cases. Among 521 nonhematologic malignancies, DAK-Pax5 reacted with 22/399 carcinomas (4/11 neuroendocrine, 2/4 Merkel-cell, 4/21 prostatic, 1/11 urothelial, 1/26 renal, 2/12 cervical squamous-cell, 3/13 ovarian, and 5/75 colonic). When compared with clone 24, DAK-Pax5 produced a stronger positivity in most if not all B-NHLs and HLs. No cross-reactivity with the anti-PAX2 antibody was recorded. DISCUSSION: DAK-Pax5 represents a new reliable tool for diagnostics and research.
PMID: 20697266 [PubMed - as supplied by publisher]
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Establishment of an erythroid cell line from primary CD36(+) erythroid progenitor cells.
Exp Hematol. 2010 Aug 6;
Authors: Wong S, Keyvanfar K, Wan Z, Kajigaya S, Young NS, Zhi N
OBJECTIVE: Most continuous cell lines with erythroid characteristics are derived from patients with myelogenous leukemia or erythroleukemia. Among them, a few cell lines have been reported to be positive for CD36. We tried to establish a continuous erythroid cell line from the primary CD36(+) erythroid progenitor cells (EPCs) by the lentivirus-mediated gene transduction system. MATERIALS AND METHODS: A Lentiviral vector carrying SV40T, hTERT, or the human papillomavirus type 16 (HPV16) E6 and E7 (E6/E7) viral oncogenes, was introduced into CD36(+) EPCs, singularly or combined. Transformed cells were characterized in terms of histology, phenotype, karyotype, and gene expression profile. RESULTS: The lentiviral vector carrying HPV16 E6/E7 genes successfully transformed CD36(+) EPCs, creating a continuous cell line, CD36E. Immunophenotype analysis revealed that the CD36E cells had characteristics of erythroid progenitors, among which about 27% of the cell population produced hemoglobin. Colony-forming cell assay demonstrated that the CD36E cells were capable of forming erythroid colonies. Using cytokines or chemical agents, attempts were performed to induce differentiation of the CD36E cells, but were ineffective, indicating the irreversible erythroid lineage commitment of the cells. The gene expression profile of the CD36E cells displayed a marked difference from that of the CD36(+) EPCs. CONCLUSION: The continuous CD36E cell line is an erythroid progenitor cell line possessing the ability to produce hemoglobin. The CD36E cell line would be an excellent tool for applied research involving erythroid lineage cells as well as comparative studies with primary CD36(+) EPCs.
PMID: 20696208 [PubMed - as supplied by publisher]
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Cost-effectiveness study comparing imatinib with interferon-alpha for patients with newly diagnosed chronic-phase (CP) chronic myeloid leukemia (CML) from the Chinese public health-care system perspective (CPHSP).
Value Health. 2009 Nov-Dec;12 Suppl 3:S85-8
Authors: Chen Z, Wang C, Xu X, Feng W
OBJECTIVE: Imatinib, a breakthrough oral molecular-targeted therapy, has demonstrated durable responses and significant survival advantage compared with interferon-based treatment. This study compares imatinib with interferon in newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) patients from the Chinese public health-care system perspective (CPHSP). METHODS: One-year cost responder and lifetime cost-utility analyses were conducted, respectively. Complete cytogenetic response was used to define a responder. Direct medical costs were included. Response rates as well as survival estimates were obtained from published literature. RESULTS: The cost per responder for interferon was close to 20 times higher than that for imatinib. The cost per additional responder was RMB36,545. The incremental cost-effectiveness ratio (ICER) comparing imatinib with interferon was RMB73,674 (95% confidence interval RMB67,712-RMB79,637) per quality-adjusted life-year. CONCLUSION: In newly diagnosed CML-CP, the cost per responder for patients treated with imatinib is much lower than that for patients treated with interferon. In the cost-utility analysis, the ICER is below the cost-effectiveness threshold recommended by the World Health Organization for developing countries. Therefore, imatinib is more cost-effective than interferon from the CPHSP.
PMID: 20586990 [PubMed - indexed for MEDLINE]
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Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells.
Cancer Sci. 2010 Jul;101(7):1577-81
Authors: Naka K, Hoshii T, Hirao A
Although discovery of the tyrosine kinase inhibitor (TKI) imatinib mesylate has significantly improved the prognosis of chronic myeloid leukemia (CML) patients, a rare population of CML stem cells is known to be resistant to TKI therapy, causing recurrence of CML. However, recent progress in CML stem cell biology may present a novel therapeutic avenue for CML patients. In this review, we focus on mechanisms used by CML stem cells to maintain TKI-resistance. Comprehensive approaches including mouse genetics, prospective identification of CML stem cells, and syngenic transplantation techniques have identified several key molecules or signaling pathways, including hedgehog (Hh)/Smo, promyelocytic leukemia (PML), 5-lipoxygenase (5-LO), and forkhead box class O (FOXO), that function in CML stem cell maintenance. Inhibiting some of these factors in combination with TKI administration successfully antagonized resistance of CML stem cells to TKI therapy, resulting in efficient eradication of leukemia cells in vivo. Thus, development of methods that sensitize CML stem cells to TKI therapy may lead to novel therapies to treat CML patients.
PMID: 20491777 [PubMed - indexed for MEDLINE]
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