Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1654-1654

Abstract: Acute lymphoblastic leukemia (ALL) is a life-threatening hematopoietic neoplasm characterized by abnormal growth and accumulation of lymphatic blast cells in various hematopoietic tissues. In a substantial number of patients, the Philadelphia (Ph) chromosome and the related oncoprotein BCR/ABL, are detectable. Despite recent advances in the management and therapy of patients with ALL, including the use of BCR/ABL1 tyrosine kinase inhibitors (TKI), the prognosis is still poor. Therefore, several attempts have been made to improve targeted treatment approaches in ALL. One strategy is to identify markers and targets expressed on leukemic stem cells (LSC) in these patients and to apply targeted drugs in order to eliminate LSC. In patients with Ph+ ALL, the leukemia-initiating cell-population is considered to reside within a CD34+/CD38- fraction of the clone. In the present study, we examined the expression of various stem cell markers and target antigens in CD34+/CD38- stem cells and in more mature CD34+/CD38+ progenitor cells in patients with Ph+ ALL (n=12), Ph- ALL (n=13), Ph+ CML (n=20), and in control bone marrow (BM) samples (unexplained cytopenia, n=10). Surface expression of target antigens was analyzed by multicolor flow cytometry, and mRNA expression levels by qPCR. As assessed by flow cytometry, CD34+/CD38- cells were found to co-express CD19, the stem cell-homing receptor CD44, the Campath-1 antigen (CD52), AC133 (CD133), FLT3 (CD135), and CXCR4 (CD184) in all ALL patients examined. In a majority of the ALL patients tested (14/25), LSC also expressed Siglec-3 (CD33). In CML, LSC were found to express a similar profile of antigens, including CD33, CD44, CD52, CD133, CD135, and CXCR4, but these cells did not express CD19. In control BM samples, CD34+/CD38- cells expressed a similar phenotype, but the levels of CD33 and CD52 were lower compared to LSC in ALL and CML. The IL-1RAP was found to be expressed on LSC in patients with Ph+ CML and Ph+ ALL, but not on LSC in Ph- ALL or in normal BM stem cells. By contrast, the SCF receptor KIT (CD117) was found to be expressed on LSC in Ph+ CML but was hardly detectable on LSC in patients with Ph+ ALL or Ph- ALL. The IL-2RA (CD25) and the SDF-1-degrading surface enzyme dipeptidyl-peptidase IV (DPPIV=CD26) were expressed on LSC in patients with CML and in all patients with Ph+ ALL exhibiting BCR/ABL-p210, whereas in Ph+ ALL with BCR/ABL-p190, LSC variably expressed CD25, and did not express CD26. In patients with Ph- ALL and in the normal BM, CD34+/CD38- cells did not express CD25 or CD26. The target receptor CD20 was detectable on ALL LSC in 7/18 patients examined. All target receptors tested were also detectable on more mature CD34+/CD38+ progenitor cells in patients with Ph+ ALL and Ph- ALL. In consecutive studies, expression of target antigens was confirmed at the mRNA level by qPCR analyses of highly enriched ALL LSC. Finally, we were able to show that the CD52-targeting drug alemtuzumab induces rapid lysis of CD34+/CD38- ALL LSC in all patients examined (Figure). In summary, our data show that LSC in Ph+ ALL and Ph- ALL express a unique phenotype, including clinically relevant cytokine receptors and cell surface target antigens, including the Campath-1 antigen, CD52. In Ph+ ALL with BCR/ABL-p210, the phenotype of ALL LSC largely resembles the phenotype of LSC in Ph+ CML, confirming the close relationship and similar pathogenesis of these two types of leukemias. Ficoll-isolated MNC of 4 patients with Ph+ ALL were incubated in control medium (Co) or in various concentrations of alemtuzumab (10-300 µg/ml) in RPMI 1640 medium in the presence of 30% human serum at 37°C for 1 hour. After washing, cells were stained with fluorochrome-conjugated mAb against CD34, CD38 and CD45 for 15 minutes. DAPI-staining was used to evaluate the percentage of viable cells. Cells were analysed using a FACSCanto II and FlowJo software. Results show the numbers of viable CD34+/CD38- cells and are expressed as percent of control (Co). Values represent the mean±S.D. of four independent experiments. Asterisk (*): p 〈 0.05 compared to control. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1654.1654

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 961-961

Abstract: Abstract 961 In Philadelphia-positive (Ph+) chronic myeloid leukemia (CML), leukemic stem cells (LSC) supposedly reside in a CD34+/CD38−/Lin− fraction of the leukemic clone. However, little is known about phenotypic properties of LSC in CML. We screened for novel LSC markers and targets in CML by gene chip studies and extensive flow cytometry analyses using monoclonal antibodies against various surface antigens (n=50). A total number of 240 bone marrow or peripheral blood samples (CML, n=95; AML, n=103; CMML, n=10, control marrow, n=32) were examined. In common with normal SC, CD34+/CD38− CML LSC were found to co-express the homing-receptor CD44, G-CSF-R (CD114), KIT (CD117), FLT3 (CD135), and CXCR4 (CD184). Similar to LSC in AML and CMML, CML LSC were found to display higher levels of Siglec-3 (CD33) and IL-3RA (CD123). Most significantly, however, we found that in contrast to normal CD34+/CD38− stem cells, CD34+/CD38− CML LSC aberrantly express IL-2RA (CD25), dipeptidylpeptidase IV (DPPIV=CD26), and IL-1RAP. In other myeloid leukemias (AML, CMML), CD34+/CD38− LSC also co-expressed CD25, but usually did not express CD26 or IL-1RAP. Whereas CD26 was expressed almost invariably on CD34+/CD38− cells in all CML patients tested, the surface enzyme was neither detectable in more mature CD34+/CD38+ progenitor cells nor on CD34+/CD38− stem cells in reactive bone marrow or healthy controls. During successful treatment with imatinib or nilotinib (patients examined at CCyR and/or MMR), CD34+/CD38− stem cells invariably showed a ‘normal' phenotype (CD25−, CD26−, IL-1RAP−), whereas in relapsing CML, CD34+/CD38− cells were again found to co-express CD25 and CD26. Sorted Lin−/CD26− stem cells obtained from CML patients (at diagnosis) engrafted irradiated NOD-SCID IL-2Rγ−/− (NSG) mice with normal multilineage BCR/ABL1− hematopoiesis, whereas Lin−/CD26+ stem cells were found to engraft NSG mice with BCR/ABL+ cells. We next examined the regulation of expression of CD25 and CD26 on CML LSC. Whereas expression of CD25 was found to depend on BCR/ABL1 and STAT5-activity, CD26 expression was found to be expressed independent of BCR/ABL1 and independent of STAT5-signaling. In a next step, we examined the potential function of CD26 on CML LSC. In these studies, CD26 was identified as a target-enzyme disrupting the niche-related SDF-1α/CXCR4 axis by degrading SDF-1α. Correspondingly, CD26-targeting gliptins (sitagliptin, 1 μM; vildagliptin, 1 μM) were found to revert recombinant DPPIV/CD26-induced or cellular CD26-induced inhibition of SDF-1α-mediated in vitro migration of CD26+ leukemic cells. Finally, we found that in a CML patient treated with nilotinib, in whom uncontrolled diabetes mellitus required therapy with saxagliptin, BCR/ABL1 levels (in percent of ABL according to IS) that were found to increase before the start of saxagliptin (IS before saxagliptin: 1.6 [-4 months], 2.3 [-3 months] , and 2.4 [at therapy-start]), decreased over time during saxagliptin-therapy (IS: 1.0 [+1 month] , 1.0 [+3 months], 0.8 [+5 months] ). Together, the CML-initiating LSC is a CD34+/CD38− cell that exhibits aberrant expression of IL-1RAP, CD25, and DPPIV/CD26. All three markers may be useful for purification of CML LSC. DPPIV/CD26 appears to be a functionally and pathogenetically relevant antigen that may facilitate niche-independent uncontrolled redistribution and thus extramedullary spread of LSC and LSC-derived progenitor cells in CML. Whether CD26 can be developed as a novel therapeutic target in CML is currently under investigation. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.961.961

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5425-5425

Abstract: In chronic myeloid leukemia (CML), the occurrence of BCR-ABL1 T315I is associated with resistance against first- and second-generation BCR-ABL1 tyrosine kinase inhibitors (TKI). Ponatinib is a third generation TKI that exerts strong anti-neoplastic effects in advanced CML and is capable of suppressing the kinase activity of BCR-ABL1 T315I. However, therapy with ponatinib is associated with potentially severe side effects. In addition, resistance against ponatinib may develop in sub-clones carrying multiple (compound) mutations in BCR-ABL1. In addition, BCR-ABL1-independent oncogenic pathways contribute to drug resistance. For these patients, alternative therapies such as stem cell transplantation (SCT) or various drug combinations are often considered.Hydroxyurea (HU) is used for initial or palliative cytoreduction in CML. However, the effects of HU on TKI-resistant mutant sub-clones have not been examined so far. The aims of this study were to explore the effects of HU on CML clones carrying BCR-ABL1 T315I as individual mutation or in compound-context, and to investigate anti-leukemic effects of the drug combination ponatinib+HU. In in vitro studies, primary patient-derived cells, human CML cell lines (K562, KU812, KCL-22), and Ba/F3 cells expressing wild type (wt) BCR-ABL1, BCR-ABL1 T315I, or BCR-ABL1 compound mutants involving T315 were examined. Cell proliferation was quantified by measuring 3H-thymidine uptake. Drug effects on competitive clonal growth were analyzed by mixing two Ba/F3 clones, one expressing BCR-ABL1 T315I with GFP and one BCR-ABL1 T315I/E255V labeled by tdTomato, at a 1:1 ratio. Then, cells were exposed to HU, pontinib, or HU+ponatinib for 72 hours, and the percentage of viable cells in each clone was analyzed by flow cytometry. The in vivo response of primary CML cells carrying BCR-ABL1 T315I to HU was examined in 4 TKI-resistant CML patients who were treated with HU (1-3 g/day) for up to 18 months. In these patients, we measured white blood counts (WBC), differential counts, and BCR-ABL1 transcript levels in peripheral blood (PB) by qPCR. The percentage of BCR-ABL1 T315I compared to total BCR-ABL1 was determined by ligation-dependent PCR. In all 4 patients treated with HU, WBC and total BCR-ABL1 mRNA levels remained stable for 3-12 months. Surprisingly, in 3 of 4 patients, the leukemic sub-clone expressing BCR-ABL1 T315Iwas no longer detectable after HU-treatment. After 3 months, 2/4 patients received allogenic SCT. In the other 2 patients, the disease remained stable for 6 and 12 months, respectively. In our in vitro studies, HU was found to inhibit the growth of all BCR-ABL1+ cell lines, including K562 (IC50: 1120±89 µM), KU812 (IC50: 216±32 µM), and KCL-22 (IC50: 196±23 µM) as well as Ba/F3 cells harboring BCR-ABL1 T315I as single mutation (IC50: 74±25 µM) or as compound together with E255V (IC50: 86±2 µM), F311L (IC50: 76±20 µM), F359V (IC50: 69±10 µM), or G250E (IC50: 89±4 µM). Interestingly, Ba/F3 cells exhibiting BCR-ABL1 T315I alone or in compound configuration were more sensitive to HU compared to Ba/F3 cells expressing wt BCR-ABL1 (IC50: 236±49 µM). As expected, HU was also found to inhibit growth of primary CML cells. In subsequent experiments, HU and ponatinib were found to synergize with each other in inhibiting growth of K562, KU812, and KCL-22 cells as well as Ba/F3 cells carrying BCR-ABL1 T315I (Figure) or BCR-ABL1-T315I/F359V. In cell mix experiments, ponatinib exerted strong growth-inhibitory effects on Ba/F3-T315I cells but not on Ba/F3-T315I/E255V cells, whereas HU was found to produce stronger effects on Ba/F3-T315I/E255V cells, and only the combination of both drugs resulted in complete suppression of both cell lines. In conclusion, HU exerts strong sub-clone-specific anti-neoplastic effects in TKI-resistant CML cells, both in patients with BCR-ABL1 T315I+CML and in various cell line models, including sub-clones harboring BCR-ABL1 T315I as single mutation or in compound configuration. In addition, we show that HU and ponatinib produce strong synergistic anti-neoplastic effects on TKI resistant CML cells, including sub-clones carrying T315I. These observations may have clinical implications and may pave the way for more effective sub-clone-eradicating but also palliative or bridging-to-SCT concepts in advanced CML. Clinical studies are now warranted to define the exact value of the drug combination ponatinib+HU in TKI-resistant CML. Figure 1 Figure 1. Disclosures Sperr: Novartis: Honoraria; Amgen: Honoraria, Research Funding. Lion:Ariad: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. Hoermann:Ariad: Honoraria; Novartis: Honoraria; Gilead: Research Funding; Amgen: Honoraria. Deininger:CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Valent:Amgen: Honoraria; Novartis: Honoraria, Research Funding; Deciphera Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding; Ariad: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.5425.5425

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4556-4556

Abstract: Central nervous system (CNS) relapse in chronic myeloid leukemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation or in those with a generalized myeloid relapse. The BCR/ABL tyrosine kinase (TK) inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood-brain-barrier. We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations could be detected. Both patients received intrathecal liposomal cytarabine (DepoCyte®) (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other patient, consecutive treatment with dasatinib (70 mg per os twice daily) was started. In response to therapy, the clinical symptoms resolved and the leukemic cells in the CSF disappeared in both patients. After four months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse. In conclusion, ‘anatomic’ resistance against imatinib in the CNS can lead to an (isolated) myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For treatment of patients with a systemic relapse involving the CNS and for prophylaxis, second-generation BCR/ABL TK inhibitors crossing the blood-brain-barrier such as dasatinib should be considered.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.4556.4556

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1800-1800

Abstract: Nilotinib, an inhibitor of BCR/ABL1 is increasingly used to treat patients suffering from chronic myeloid leukemia (CML). However, treatment with nilotinib is associated with the occurrence of vascular adverse events, including progressive atherosclerosis resulting in arterial occlusive disease (AOD). We have recently shown that these events are recurrent and severe and accumulate over time in our patients (n=36). The percentage of patients developing i) one or more clinically overt (symptomatic) AOD-related events and ii) one or more clinically severe AOD events requiring surgical intervention and/or prolonged hospitalization increased from 26.5% and 17.6% at a median observation time (MOT) of 24 months to 44.4% and 19.4% after a MOT of 44 months. The frequency of AOD was lower in all control cohorts examined, including risk factor- and age-matched CML patients treated with imatinib, patients suffering from myelodysplastic syndromes, patients with JAK2-mutated myeloproliferative neoplasms and patients with lymphoid neoplasms. In order to explore the potential pro-atherogenic potential of nilotinib, we employed ApoE knock-out mice. In these mice, treatment with nilotinib (75 mg/kg/day p.o. for 8 weeks) was found to promote plaque formation and thus atherosclerosis when compared to control-mice (percent aortic plaque-area: vehicle-control: 16±3.2%; imatinib: 19.4±8.2%; nilotinib: 22.4±2.9%; p 〈 0.005 for nilotinib vs control). To evaluate the effects of nilotinib on vascular repair processes following stenosis, we also employed a mouse model of hindlimb ischemia. Here, nilotinib (75 mg/kg/day p.o. for 28 days) was found to decrease reperfusion after induction of ischemia whereas imatinib (100 mg/kg/day p.o. for 28 days) showed no comparable effect as determined by laser Doppler perfusion imaging. The decreased perfusion seen in the nilotinib-treated mice was accompanied by an increased rate of limb necrosis as well as a decrease in microvessel density when compared to imatinib-treated mice or control-mice (p 〈 0.05). In addition, we found that the pro-atherogenic cytoadhesion molecule VCAM-1 is expressed at higher levels in vascular cells in nilotinib-treated mice compared to imatinib-treated mice or control animals (cells/high power field: control: 13.9±11.9; imatinib: 14.9±11; nilotinib: 22.6±9.3). In a next step, we examined the in vitro effects of nilotinib on cultured human umbilical vein endothelial cells (HUVEC). In these experiments, we found that nilotinib (between 1-10 µM), but not imatinib (1-10 µM) promotes the expression of the cytoadhesion molecules ICAM-1, VCAM-1 and E-Selectin on HUVEC, confirming our data obtained in mice. In addition, we were able to confirm the anti-angiogenic effects of nilotinib seen in mice by our in vitro experiments. In particular, nilotinib was found to inhibit the migration of HUVEC in a wound-scratch assay as well as angiogenesis in a tube-formation assay whereas imatinib showed no comparable effect. Moreover, nilotinib was found to inhibit the proliferation of HUVEC in a dose-dependent manner (IC50: 1.0 µM) whereas imatinib showed no substantial effect up to 5 µM. Finally, we examined bone marrow (BM) microvessel density in 8 CML patients before and during treatment with nilotinib (800 mg/day for at least 1 year). In these experiments, we found that the numbers of CD34+ endothelial cells per high power field decreases substantially during treatment with nilotinib (before nilotinib: 12.3±2 versus post-nilotinib: 5.5±2.6, p 〈 0.05). In summary, nilotinib exerts direct proatherogenic and growth-inhibitory and thus anti-angiogenic effects on vascular endothelial cells. Whether these effects contribute to nilotinib-associated vasculopathy in patients with CML is currently under investigation. Disclosures Wolf: BMS: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Valent:Pfizer: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1800.1800

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: American Journal of Hematology, Wiley, Vol. 91, No. 12 ( 2016-12), p. 1239-1245

Abstract: Although it is generally appreciated that a subset of elderly patients with acute myeloid leukemia (AML) may benefit from intensive consolidation, little is known about variables predicting such benefit. We analyzed 192 consecutive patients with de novo AML aged ≥60 years who were treated with intensive chemotherapy. About 115 patients (60%) achieved complete hematologic remission (CR). Among several parameters, the karyotype was the only independent variable predicting CR ( P   〈  0.05). About 92% (105/115) of the CR‐patients received up to four consolidation cycles of intermediate dose ARA‐C. Median continuous CR (CCR) and disease‐free survival (DFS) were 1.3 and 1.1 years, respectively. CCR, DFS, and survival at 5 years were 23%, 18%, and 15%, respectively. Only karyotype and mutated NPM1 ( NPM1 mut) were independent predictors of survival. NPM1 mut showed a particular prognostic impact in patients with normal (CN) or non‐monosomal (Mkneg) karyotype by Haemato‐Oncology Foundation for Adults in the Netherlands (HOVON)‐criteria, or intermediate karyotype by Southwest Oncology Group (SWOG)‐criteria. The median CCR was 0.94, 1.6, 0.9, and 0.5 years for core‐binding‐factor, CN/Mkneg‐ NPM1 mut, CN/Mkneg‐ NPM1 ‐wild‐type AML, and AML with monosomal karyotype, respectively, and the 5‐year survival was 25%, 39%, 2%, and 0%, respectively ( P   〈  0.05). Similar results (0.9, 1.5, 0.9, and 0.5 years) were obtained using modified SWOG criteria and NPM1 mutation status ( P   〈  0.05). In summary, elderly patients with CN/Mkneg‐ NPM1 mut or CBF AML can achieve long term CCR when treated with intensive induction and consolidation therapy whereas most elderly patients with CN/Mkneg‐ NPM1 wt or Mkpos AML may not benefit from intensive chemotherapy. For these patients either hematopoietic‐stem‐cell‐transplantation or alternative treatments have to be considered. Am. J. Hematol. 91:1239–1245, 2016. © 2016 Wiley Periodicals, Inc.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v91.12

DOI: 10.1002/ajh.24560

Language: English

Publisher: Wiley

Publication Date: 2016

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 11634-11635

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-162588

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: European Journal of Internal Medicine, Elsevier BV, Vol. 20, No. 8 ( 2009-12), p. 775-778

Type of Medium: Online Resource

ISSN: 0953-6205

URL: Article

DOI: 10.1016/j.ejim.2009.09.007

Language: English

Publisher: Elsevier BV

Publication Date: 2009

detail.hit.zdb_id: 2026166-4

In: Oncotarget, Impact Journals, LLC, Vol. 7, No. 29 ( 2016-07-19), p. 46466-46481

Type of Medium: Online Resource

ISSN: 1949-2553

URL: Issue

URL: Article

DOI: 10.18632/oncotarget.v7i29

DOI: 10.18632/oncotarget.10191

Language: English

Publisher: Impact Journals, LLC

Publication Date: 2016

detail.hit.zdb_id: 2560162-3

In: Oncotarget, Impact Journals, LLC, Vol. 6, No. 5 ( 2015-02-20), p. 3071-3084

Type of Medium: Online Resource

ISSN: 1949-2553

URL: Issue

URL: Article

DOI: 10.18632/oncotarget.v6i5

DOI: 10.18632/oncotarget.3074

Language: English

Publisher: Impact Journals, LLC

Publication Date: 2015

detail.hit.zdb_id: 2560162-3