Publications by authors named "Karl J Aichberger"

32 Publications

Adrenal crisis in metastatic breast cancer.

BMJ Case Rep 2017 Jul 6;2017. Epub 2017 Jul 6.

Interne I: Internistische Onkologie, Hämatologie u. Gastroenterologie, Ordensklinikum Linz Krankenhaus d. Barmherzigen Schwestern Linz Betriebs GmbH, Linz, Austria.

A female patient with oestrogen receptor-positive and human epidermal growth factor receptor 2 (HER2)-positive invasive lobular breast cancer presented with progressive disease on CT scan. Some days after initiation of antineoplastic chemotherapy and anti-HER2 targeted antibody therapy, the patient presented with profuse diarrhoea, neutropaenia, nausea and weakness. Although was rapidly tackled as a causative agent of gastrointestinal complaints, clinical situation did not markedly improve despite proper antimicrobial treatment. The patient reported profound lack of energy, while nausea, vomiting and loose stools still persisted. Additionally slightly exaggerated pigmentation of nonsunexposed skin and mucosal areas led us to the assumption of proopiomelanocortin-derived peptide hypersecretion. The combination of highly elevated adrenocorticotropic hormone and low basal cortisol levels taken from a morning blood sample established the diagnosis of adrenal insufficiency due to metastatic burden, leading to a near Addison crisis by gastrointestinal complications of chemo-immune therapy. Administration of hydrocortisone immediately relieved general symptoms .
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http://dx.doi.org/10.1136/bcr-2017-220284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535009PMC
July 2017

Taxan-associated nail toxicity.

BMJ Case Rep 2017 Jan 31;2017. Epub 2017 Jan 31.

Krankenhaus der Barmherzigen Schwestern Linz, Linz, Austria.

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http://dx.doi.org/10.1136/bcr-2016-218980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293967PMC
January 2017

Disseminated Histoplasmosis: A Challenging Differential Diagnostic Consideration for Suspected Malignant Lesions in the Digestive Tract.

Case Rep Gastroenterol 2016 Sep-Dec;10(3):653-660. Epub 2016 Nov 7.

Department of Internal Medicine I, Hematology, Oncology and Gastroenterology, Hospital of the Sisters of Charity, Linz, Austria.

Histoplasmosis is well characterized as an endemic fungal disease restricted to certain areas of the USA. In Middle Europe, most patients present with acute pulmonary symptoms after travelling to endemic areas. Here, we want to illustrate the case of a 67-year-old man who presented with persistent oral ulcers, hoarseness, dysphagia, diarrhea, and weight loss to our Department of Otorhinolaryngology in December 2014. He was a retired construction worker and had a history of soil-disruptive activities in Africa and Middle and South America during employment. A positron emission tomography-computed tomography scan revealed prominent hypermetabolic lesions in the cecum and the lung, pointing towards a malignant disease. Surprisingly, histological examination of colonic and oral biopsies revealed abundant intracellular fungal elements, highly suspicious of . Diagnosis was finally confirmed by panfungal polymerase chain reaction. Upon treatment with liposomal amphotericin followed by itraconazole, the severely ill patient showed an impressive clinical response. This case describes a disseminated manifestation of years after the first exposure in an otherwise immunocompetent patient descending from a nonendemic area.
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http://dx.doi.org/10.1159/000452203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126600PMC
November 2016

Identification of basophils as a major source of hepatocyte growth factor in chronic myeloid leukemia: a novel mechanism of BCR-ABL1-independent disease progression.

Neoplasia 2012 Jul;14(7):572-84

Ludwig Boltzmann Cluster Oncology, Vienna, Austria.

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421954PMC
http://dx.doi.org/10.1593/neo.12724DOI Listing
July 2012

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms.

Blood 2011 Dec 22;118(24):6392-8. Epub 2011 Aug 22.

Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.

Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2(V617F) expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2(V617F)-positive MPN. Altogether our data are consistent with a model where JAK2(V617F) promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.
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http://dx.doi.org/10.1182/blood-2011-04-348144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236121PMC
December 2011

Effectiveness of preventive measures for hemato-oncologic patients undergoing stem cell transplantation during a period of hospital construction.

Am J Infect Control 2011 Nov 25;39(9):746-51. Epub 2011 Jun 25.

Division of Hospital Hygiene, Clinical Institute for Hygiene and Medical Microbiology, Medical University Vienna, Austria.

Background: Aspergillus spp are ubiquitous spore-forming fungi. Construction work, renovation, demolition, or excavation activities within a hospital or in surrounding areas increase the risk for aspergillus infection in susceptible patients and are the main cause of nosocomial aspergillus outbreaks.

Methods: We investigated the efficacy of infection control measures on the frequency of fungal infection among hemato-oncologic patients undergoing stem cell transplantation during excavation and construction work of an adjacent hospital building. Clinical isolates from these patients obtained before and during the excavation and construction period were analyzed. Preventive measures consisted in the implementation of a multibarrier concept to protect these patients from fungal infection.

Results: There was no record of any clinical isolate of Aspergillus spp in the observation period before the beginning of the groundwork. However, 3 clinically significant isolates of Aspergillus spp were detected in respiratory tract specimen of 2 patients after the beginning of excavation and demolition work, which were found to be community acquired.

Conclusion: Although our data cannot demonstrate the efficacy of infection control measures during construction work, it can be concluded that excavation work close to immunocompromised patients is safe if a bundle of preventive measures is implemented before groundwork.
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http://dx.doi.org/10.1016/j.ajic.2011.01.011DOI Listing
November 2011

Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML.

Am J Hematol 2011 Jul 27;86(7):533-9. Epub 2011 Apr 27.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.

The second generation BCR/ABL kinase inhibitor nilotinib is increasingly used for the treatment of imatinib-resistant chronic myeloid leukemia (CML). So far, nilotinib is considered a well-tolerated drug with little if any side effects, although an increase in the fasting glucose level has been reported. We examined a series of 24 consecutive CML patients treated with nilotinib in our center for the development of non-hematologic adverse events. Three of these 24 CML patients developed a rapidly progressive peripheral arterial occlusive disease (PAOD) during treatment with nilotinib. In all three cases, PAOD required repeated angioplasty and/or multiple surgeries within a few months. No PAOD was known before nilotinib-therapy in these patients, although all three had received imatinib. In two patients, pre-existing risk factors predisposing for PAOD were known, and one of them had developed diabetes mellitus during nilotinib. In the other 21 patients treated with nilotinib in our center, one less severe PAOD, one myocardial infarction, one spinal infarction, one subdural hematoma, and one sudden death of unknown etiology were recorded. In summary, treatment with nilotinib may be associated with an increased risk of vascular adverse events, including PAOD development. In a subgroup of patients, these events are severe or even life-threatening. Although the exact mechanisms remain unknown, we recommend screening for pre-existing PAOD and for vascular risk factors such as diabetes mellitus in all patients before starting nilotinib and in the follow up during nilotinib-therapy.
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http://dx.doi.org/10.1002/ajh.22037DOI Listing
July 2011

A matched prospective cohort study on Staphylococcus aureus and Escherichia coli bloodstream infections: extended perspectives beyond resistance.

Am J Infect Control 2010 Dec 22;38(10):839-45. Epub 2010 Jul 22.

Division of Hospital Hygiene, Clinical Institute for Hygiene and Medical Microbiology, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria.

Background: Bacteremias caused by Staphylococcus aureus and Escherichia coli are among the most common bloodstream infections (BSIs) in adults. The aim of the study was to investigate risk factors for infection and clinical outcomes of bacteremias caused by S aureus or E coli.

Methods: We conducted a 1-year matched prospective cohort study including 150 patients with BSI caused by susceptible or resistant S aureus or E coli and 300 controls without BSI caused by these organisms.

Results: Of the 150 episodes of bacteremia, 37% were caused by S aureus (including 5 cases of methicillin-resistant S aureus [MRSA]) and 63% were caused by E coli (including 9 cases of extended-spectrum beta lactamase [ESBL]-producing E coli). We identified 4 independent risk factors for acquisition of S aureus bacteremia (emergency, peripheral or central vascular catheter, renal disease) and 6 risk factors for E coli bacteremia (emergency, peripheral or central vascular catheter, malignancy, cytoreductive or immunosuppressive therapy). Both types of bacteremia were associated with an increased length of hospital stay compared with controls. We observed a 5-fold increase in the 30-day mortality rate for bacteremias due to S aureus, and a 2-fold increase in BSI caused by E coli. The in-hospital mortality rate was increased by 6-fold for S aureus and by 3-fold for E coli.

Conclusion: Longer hospitalization periods and increased mortality of bacteremias caused by S aureus or E coli, irrespective of susceptibility, implicate controlling for risk factors at an early stage.
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http://dx.doi.org/10.1016/j.ajic.2010.04.212DOI Listing
December 2010

CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms.

Blood 2010 Jun 12;115(25):5232-40. Epub 2010 Apr 12.

Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.

Activating alleles of Janus kinase 2 (JAK2) such as JAK2(V617F) are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5muM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2(V617F) allele burden, JAK2(V617F) cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2(V617F) cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells.
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http://dx.doi.org/10.1182/blood-2009-05-223727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892953PMC
June 2010

Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs.

Blood 2009 Dec 22;114(26):5342-51. Epub 2009 Oct 22.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In most cases, neoplastic cells display the D816V-mutated variant of KIT. KIT D816V exhibits constitutive tyrosine kinase (TK) activity and has been implicated in increased survival and growth of neoplastic MCs. Recent data suggest that the proapoptotic BH3-only death regulator Bim plays a role as a tumor suppressor in various myeloid neoplasms. We found that KIT D816V suppresses expression of Bim in Ba/F3 cells. The KIT D816-induced down-regulation of Bim was rescued by the KIT-targeting drug PKC412/midostaurin. Both PKC412 and the proteasome-inhibitor bortezomib were found to decrease growth and promote expression of Bim in MC leukemia cell lines HMC-1.1 (D816V negative) and HMC-1.2 (D816V positive). Both drugs were also found to counteract growth of primary neoplastic MCs. Furthermore, midostaurin was found to cooperate with bortezomib and with the BH3-mimetic obatoclax in producing growth inhibition in both HMC-1 subclones. Finally, a Bim-specific siRNA was found to rescue HMC-1 cells from PKC412-induced cell death. Our data show that KIT D816V suppresses expression of proapoptotic Bim in neoplastic MCs. Targeting of Bcl-2 family members by drugs promoting Bim (re)-expression, or by BH3-mimetics such as obatoclax, may be an attractive therapy concept in SM.
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http://dx.doi.org/10.1182/blood-2008-08-175190DOI Listing
December 2009

Same mutation, different allele.

Blood 2009 Oct;114(14):2853-4

Oregon Health & Science University, USA.

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http://dx.doi.org/10.1182/blood-2009-07-229906DOI Listing
October 2009

Unique effects of KIT D816V in BaF3 cells: induction of cluster formation, histamine synthesis, and early mast cell differentiation antigens.

J Immunol 2008 Apr;180(8):5466-76

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Oncogenic tyrosine kinases (TK) usually convert growth factor-dependent cells to factor independence with autonomous proliferation. However, TK-driven neoplasms often are indolent and characterized by cell differentiation rather than proliferation. A prototype of an indolent TK-driven neoplasm is indolent systemic mastocytosis. We found that the D816V-mutated variant of KIT, a TK detectable in most patients with systemic mastocytosis, induces cluster formation and expression of several mast cell differentiation and adhesion Ags, including microphthalmia transcription factor, IL-4 receptor, histamine, CD63, and ICAM-1 in IL-3-dependent BaF3 cells. By contrast, wild-type KIT did not induce cluster formation or mast cell differentiation Ags. Additionally, KIT D816V, but not wild-type KIT, induced STAT5 activation in BaF3 cells. However, despite these intriguing effects, KIT D816V did not convert BaF3 cells to factor-independent proliferation. Correspondingly, BaF3 cells with conditional expression of KIT D816V did not form tumors in nude mice. Together, the biologic effects of KIT D816V in BaF3 cells match strikingly with the clinical course of indolent systemic mastocytosis and with our recently established transgenic mouse model, in which KIT D816V induces indolent mast cell accumulations but usually does not induce a malignant mast cell disease. Based on all these results, it is hypothesized that KIT D816V as a single hit may be sufficient to cause indolent systemic mastocytosis, whereas additional defects may be required to induce aggressive mast cell disorders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976849PMC
http://dx.doi.org/10.4049/jimmunol.180.8.5466DOI Listing
April 2008

The IgE-reactive autoantigen Hom s 2 induces damage of respiratory epithelial cells and keratinocytes via induction of IFN-gamma.

J Invest Dermatol 2008 Jun 13;128(6):1451-9. Epub 2007 Dec 13.

Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria.

Hom s 2, the alpha-chain of the nascent polypeptide-associated complex, is an intracellular autoantigen that has been identified with IgE autoantibodies from atopic dermatitis patients. We investigated the humoral and cellular immune response to purified recombinant Hom s 2 (rHom s 2). rHom s 2 exhibited IgE reactivity comparable to exogenous allergens, but did not induce relevant basophil cell degranulation. The latter may be attributed to the fact that patients recognized single epitopes on Hom s 2 as revealed by IgE epitope mapping with rHom s 2 fragments. In contrast to exogenous allergens, rHom s 2 had the intrinsic ability to induce the release of IFN-gamma in cultured peripheral blood mononuclear cells from atopic as well as non-atopic individuals. IFN-gamma-containing culture supernatants from Hom s 2-stimulated peripheral blood mononuclear cells caused disintegration of respiratory epithelial cell layers and apoptosis of skin keratinocytes, which could be inhibited with a neutralizing anti-IFN-gamma antibody. Our data demonstrate that the Hom s 2 autoantigen can cause IFN-gamma-mediated cell damage.
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http://dx.doi.org/10.1038/sj.jid.5701195DOI Listing
June 2008

Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib.

Blood 2008 Feb 16;111(4):2200-10. Epub 2007 Nov 16.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Resistance toward imatinib and other BCR/ABL tyrosine kinase inhibitors remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CML). We recently have identified the heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) as a BCR/ABL-dependent survival molecule in CML cells. We here show that silencing Hsp32/HO-1 in CML cells by an siRNA approach results in induction of apoptosis. Moreover, targeting Hsp32/HO-1 by either pegylated zinc protoporphyrine (PEG-ZnPP) or styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP) resulted in growth inhibition of BCR/ABL-transformed cells. The effects of PEG-ZnPP and SMA-ZnPP were demonstrable in Ba/F3 cells carrying various imatinib-resistant mutants of BCR/ABL, including the T315I mutant, which exhibits resistance against all clinically available BCR/ABL tyrosine kinase inhibitors. Growth-inhibitory effects of PEG-ZnPP and SMA-ZnPP also were observed in the CML-derived human cell lines K562 and KU812 as well as in primary leukemic cells obtained from patients with freshly diagnosed CML or imatinib-resistant CML. Finally, Hsp32/HO-1-targeting compounds were found to synergize with either imatinib or nilotinib in producing growth inhibition in imatinib-resistant K562 cells and in Ba/F3 cells harboring the T315I mutant of BCR/ABL. In summary, these data show that HO-1 is a promising novel target in imatinib-resistant CML.
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http://dx.doi.org/10.1182/blood-2006-11-055723DOI Listing
February 2008

Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT.

Haematologica 2007 Nov;92(11):1451-9

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.

Background And Objectives: In a majority of all patients with systemic mastocytosis (SM) including those with mast cell leukemia (MCL), neoplastic mast cells (MC) display the D816V-mutated variant of KIT. The respective oncoprotein, KIT D816V, exhibits constitutive tyrosine kinase (TK) activity and has been implicated in malignant cell growth. Therefore, several attempts have been made to identify KIT D816V-targeting drugs.

Design And Methods: We examined the effects of the novel TK-inhibitor dasatinib alone and in combination with other targeted drugs on growth of neoplastic MC.

Results: Confirming previous studies, dasatinib was found to inhibit the TK activity of wild type (wt) KIT and KIT-D816V as well as growth and survival of neoplastic MC and of the MCL cell line, HMC-1. The growth-inhibitory effects of dasatinib in HMC-1 cells were found to be associated with a decrease in expression of CD2 and CD63. In addition, we found that dasatinib blocks KIT D816V-induced cluster-formation and viability in Ba/F3 cells. In drug combination experiments, dasatinib was found to co-operate with PKC412, AMN107, imatinib, and 2CdA in producing growth-inhibition and apoptosis in neoplastic MC. In HMC-1.1 cells lacking KIT D816V, all drug interactions were found to be synergistic in nature. By contrast, in HMC-1.2 cells exhibiting KIT D816V, only the combinations dasatinib+PKC412 and dasatinib+2CdA were found to produce synergistic effects.

Interpretation And Conclusions: Combinations of targeted drugs may represent an interesting pharmacologic approach for the treatment of aggressive SM or MCL.
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http://dx.doi.org/10.3324/haematol.11339DOI Listing
November 2007

Myeloid leukemias express a broad spectrum of VEGF receptors including neuropilin-1 (NRP-1) and NRP-2.

Leuk Lymphoma 2007 Oct;48(10):1997-2007

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and may act as an autocrine growth-regulator. We have examined the expression of five VEGF receptors (VEGR1/Flt-1, VEGFR2/KDR, Flt-4, neuropilin-1 = NRP-1, NRP-2) in leukemic cells obtained from patients with acute myeloid leukemia (n = 28), chronic myeloid leukemia (n = 14), chronic eosinophilic leukemia (n = 3), chronic myelomonocytic leukemia (n = 9), or mast cell leukemia/systemic mastocytosis (n = 3) as well as in respective cell lines. Expression of VEGFR mRNA was analyzed by RT-PCR, and expression of VEGFR protein by immunocytochemistry. In most patients, leukemic cells expressed NRP-1 mRNA and NRP-2 mRNA independent of the type of disease. By contrast, transcripts for Flt-1, KDR, and Flt-4 were expressed variably without a clear correlation to the type of leukemia. Expression of VEGF receptors was also demonstrable at the protein level in all cases tested. In conclusion, neoplastic cells in myeloid leukemias frequently express VEGFR including NRP-1 and NRP-2.
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http://dx.doi.org/10.1080/10428190701534424DOI Listing
October 2007

Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells.

Blood 2007 Jul 9;110(2):661-9. Epub 2007 Apr 9.

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Graduate School of Medical Sciences, Kumamoto University, Japan.

Systemic mastocytosis (SM) is a myeloid neoplasm characterized by increased survival and accumulation of neoplastic mast cells (MCs). In most patients, the D816V-mutated variant of KIT is detectable. We report here that heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a novel KIT-inducible survival factor in neoplastic MCs. As assessed by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry, and Western blotting, the KIT D816V(+) MC line HMC-1.2 as well as highly enriched primary neoplastic MCs were found to express Hsp32 mRNA and the Hsp32 protein. Moreover, KIT D816V and stem cell factor (SCF)-activated wild-type KIT were found to induce Hsp32 promoter activity, expression of Hsp32 mRNA, and expression of the Hsp32 protein in Ba/F3 cells. Correspondingly, the KIT D816V-targeting drug PKC412 decreased the expression of Hsp32 as well as proliferation/survival in neoplastic MCs. The inhibitory effects of PKC412 on the survival of HMC-1.2 cells were counteracted by the HO-1 inductor hemin or lentiviral-transduced HO-1. Moreover, 2 Hsp32-targeting drugs, pegylated zinc protoporphyrin (PEG-ZnPP) and styrene maleic acid copolymer micelle-encapsulated ZnPP (SMA-ZnPP), were found to inhibit proliferation and to induce apoptosis in neoplastic MCs. Furthermore, both drugs were found to cooperate with PKC412 in producing growth inhibition. Together, these data show that Hsp32 is an important survival factor and interesting new therapeutic target in neoplastic MCs.
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http://dx.doi.org/10.1182/blood-2006-10-054411DOI Listing
July 2007

Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412.

Blood 2007 Apr;109(7):3031-41

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.

MCL-1 is a Bcl-2 family member that has been described as antiapoptotic in various myeloid neoplasms. Therefore, MCL-1 has been suggested as a potential new therapeutic target. Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In the present study, we examined the expression and functional role of MCL-1 in neoplastic MCs and sought to determine whether MCL-1 could serve as a target in SM. As assessed by RT-PCR and immunohistochemical examination, primary neoplastic MCs expressed MCL-1 mRNA and the MCL-1 protein in all SM patients examined. Moreover, MCL-1 was detectable in both subclones of the MC line HMC-1--HMC-1.1 cells, which lack the SM-related KIT mutation D816V, and HMC-1.2 cells, which carry KIT D816V. Exposure of HMC-1.1 cells or HMC-1.2 cells to MCL-1-specific antisense oligonucleotides (ASOs) or MCL-1-specific siRNA resulted in reduced survival and increased apoptosis compared with untreated cells. Moreover, MCL-1 ASOs were found to cooperate with various tyrosine kinase inhibitors in producing growth inhibition in neoplastic MCs, with synergistic effects observed with PKC412, AMN107, and imatinib in HMC-1.1 cells and with PKC412 in HMC-1.2 cells. Together, these data show that MCL-1 is a novel survival factor and an attractive target in neoplastic MCs.
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http://dx.doi.org/10.1182/blood-2006-07-032714DOI Listing
April 2007

The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells.

Blood 2006 Nov 18;108(10):3538-47. Epub 2006 Jul 18.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, AKH-Wien, Waehringer Guertel 18-20, A-1090 Vienna, Austria.

Basophil numbers are typically elevated in chronic myeloid leukemia (CML) and increase during disease progression. Histamine is an essential mediator and marker of basophils and is highly up-regulated in CML. We examined the biochemical basis of histamine synthesis in CML cells. The CML-specific oncoprotein BCR/ABL was found to promote expression of histidine decarboxylase (HDC) and synthesis of histamine in Ba/F3 cells. Moreover, the BCR/ABL tyrosine kinase inhibitors imatinib (STI571) and nilotinib (AMN107) decreased histamine levels and HDC mRNA expression in BCR/ABL-transformed Ba/F3 cells, in the CML-derived basophil cell line KU812, and in primary CML cells. Synthesis of histamine was found to be restricted to the basophil compartment of the CML clone and to depend on signaling through the PI3-kinase pathway. CML cells also expressed histamine receptors (HRs), including HR-1, HR-2, HR-4, and histamine-binding CYP450 isoenzymes which also serve as targets of HR antagonists. The HR-1 antagonists loratadine and terfenadine, which bind to CYP450, were found to counteract proliferation of CML cells, whereas no growth inhibition was observed with the HR-1 antagonist fexofenadine which is not targeted or metabolized by CYP450. Moreover, DPPE, an inhibitor of histamine-binding CYP450 isoenzymes, produced growth inhibition in CML cells. Together, these data show that BCR/ABL promotes histamine production in CML cells and that certain HR-targeting drugs exert antileukemic effects on CML cells.
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http://dx.doi.org/10.1182/blood-2005-12-028456DOI Listing
November 2006

Evaluation of biologic activity of tryptase secreted from blast cells in acute myeloid leukemia.

Leuk Lymphoma 2006 May;47(5):897-906

Department of Internal Medicine I, Division of Hematology & Hemostaseology - the Center of Excellence for Clinical and Experimental Oncology (CLEXO), Medical University of Vienna, Austria.

A number of autocrine and paracrine growth regulators are considered to be involved in the survival and proliferation of blast cells in acute myeloid leukemia (AML). We have recently shown that blast cells in a group of patients with AML produce and secrete the mitogenic enzyme tryptase. In the present study, we examined functional effects of tryptase in the context of AML. As assessed by 3H-thymidine uptake experiments, tryptase-containing serum from patients with AML as well as heparin-complexed recombinant tryptase were found to promote the proliferation of cultured bone marrow- and lung fibroblasts in a dose-dependent manner. A neutralizing antibody against human beta-tryptase was found to diminish these growth-stimulatory effects of serum-tryptase in all patients examined. Tryptase also induced the expression of mRNA for GM-CSF and SCF, two cytokines known to promote growth of AML cells, in cultured bone marrow fibroblasts. Neither recombinant tryptase nor tryptase-rich serum of AML patients, showed an effect on the growth of leukemic blast cells irrespective of the FAB category or expression of protease-activated receptor (PAR)-2, a putative molecular target of tryptase. Together, tryptase is secreted from AML blasts as a biologically active molecule that may exhibit paracrine rather than autocrine effects in AML.
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http://dx.doi.org/10.1080/10428190500513652DOI Listing
May 2006

Immunohistochemical detection of histidine decarboxylase in neoplastic mast cells in patients with systemic mastocytosis.

Hum Pathol 2006 Apr 7;37(4):439-47. Epub 2006 Feb 7.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Austria.

Synthesis of histamine in hematopoietic progenitor cells may be one of the earliest events in mastopoiesis. We therefore asked whether the key enzyme involved in histamine production, histidine decarboxylase (HDC), can be used as an immunohistochemical marker for the detection of immature neoplastic mast cells (MC) in patients with MC-proliferative disorders. To address this question, we examined bone marrow biopsy specimens in a cohort of 102 patients with mastocytosis using an antibody against HDC. Independent of the maturation stage of MC, the anti-HDC antibody produced clear diagnostic staining results in all patients with systemic MC disease examined including those with MC leukemia and MC sarcoma, in which MCs are particularly immature. In these patients, expression of HDC was reconfirmed at the messenger RNA level by reverse transcriptase polymerase chain reaction analyses performed with RNA of highly enriched CD117(+) MC. In summary, HDC is expressed in neoplastic MC in patients with systemic mastocytosis independent of the maturation stage of cells or the variant of disease. Histidine decarboxylase should therefore be considered as a new MC marker in the screen panel of antigens used to diagnose high-grade MC malignancies.
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http://dx.doi.org/10.1016/j.humpath.2005.11.015DOI Listing
April 2006

Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the bone marrow in patients with myelodysplastic syndromes: correlation between VEGF expression and the FAB category.

Leuk Lymphoma 2006 Mar;47(3):451-60

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

Recent data suggest that vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and plays a key role as an autocrine regulator and mediator of angiogenesis. We examined the expression of VEGF in paraffin-embedded bone marrow sections obtained from normal donors (n = 5) and 46 patients with myelodysplastic syndromes [MDS, French-American-British (FAB)-type refractory anemia (RA), n = 10; refractory anemia with ringed sideroblasts (RARS), n = 10; refractory anemia with excess blasts (RAEB), n = 10; RAEB in transformation (RAEB-T), n = 8; chronic myelomonocytic leukemia (CMML), n = 8] by immunohistochemistry using an anti-VEGF antibody. In normal bone marrow, the anti-VEGF antibody was found to react with myeloid progenitor cells, immature monocytic cells, plasma cells and megakaryocytes, but not with erythroid cells or mature granulocytic cells. Higher levels of VEGF were found in patients with MDS, subtypes RAEB, RAEB-T and CMML, compared to patients with RA or RARS, or the normal bone marrow. These differences were found to result from expression of VEGF in immature myeloid cells in RAEB, RAEB-T and CMML. The microvessel density was also higher in patients with RAEB-T and CMML compared to RA and RARS or the normal bone marrow. Expression of VEGF mRNA was demonstrable in isolated neoplastic cells by reverse transcriptase-polymerase chain reaction in all patients examined. In aggregate, these data show that VEGF is expressed in bone marrow cells in patients with MDS. The amount of expressed VEGF is related to the percentage of immature myeloid cells (blasts and monocytic progenitors) and correlates with the FAB category.
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http://dx.doi.org/10.1080/10428190500353083DOI Listing
March 2006

Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia: role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds.

Cancer Res 2005 Oct;65(20):9436-44

Department of Internal Medicine I, Division of Hematology and Hemostaseology- the Center of Excellence in Clinical and Experimental Oncology.

Chronic myeloid leukemia (CML) is a myeloproliferative disease in which BCR/ABL enhances survival of leukemic cells through modulation of proapoptotic and antiapoptotic molecules. Recent data suggest that proapoptotic Bcl-2-interacting mediator (Bim) plays a role as a tumor suppressor in myeloid cells, and that leukemic cells express only low amounts of this cell death activator. We here show that primary CML cells express significantly lower amounts of bim mRNA and Bim protein compared with normal cells. The BCR/ABL inhibitors imatinib and AMN107 were found to promote expression of Bim in CML cells. To provide direct evidence for the role of BCR/ABL in Bim modulation, we employed Ba/F3 cells with doxycycline-inducible expression of BCR/ABL and found that BCR/ABL decreases expression of bim mRNA and Bim protein in these cells. The BCR/ABL-induced decrease in expression of Bim was found to be a posttranscriptional event that depended on signaling through the mitogen-activated protein kinase pathway and was abrogated by the proteasome inhibitor MG132. Interestingly, MG132 up-regulated the expression of bim mRNA and Bim protein and suppressed the growth of Ba/F3 cells containing wild-type BCR/ABL or imatinib-resistant mutants of BCR/ABL. To show functional significance of "Bim reexpression," a Bim-specific small interfering RNA was applied and found to rescue BCR/ABL-transformed leukemic cells from imatinib-induced cell death. In summary, our data identify BCR/ABL as a Bim suppressor in CML cells and suggest that reexpression of Bim by novel tyrosine kinase inhibitors, proteasome inhibition, or by targeting signaling pathways downstream of BCR/ABL may be an attractive therapeutic approach in imatinib-resistant CML.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-0972DOI Listing
October 2005

PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects.

Blood 2006 Jan 27;107(2):752-9. Epub 2005 Sep 27.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Center of Excellence in Clinical and Experimental Oncology, Institute of Immunology, Medical University of Vienna, Austria.

In most patients with systemic mastocytosis (SM), including aggressive SM and mast cell leukemia (MCL), neoplastic cells express the oncogenic KIT mutation D816V. KIT D816V is associated with constitutive tyrosine kinase (TK) activity and thus represents an attractive drug target. However, imatinib and most other TK inhibitors fail to block the TK activity of KIT D816V. We show that the novel TK-targeting drugs PKC412 and AMN107 counteract TK activity of D816V KIT and inhibit the growth of Ba/F3 cells with doxycycline-inducible expression of KIT D816V as well as the growth of primary neoplastic mast cells and HMC-1 cells harboring this KIT mutation. PKC412 was a superior agent with median inhibitory concentration (IC(50)) values of 50 to 250 nM without differences seen between HMC-1 cells exhibiting or lacking KIT D816V. By contrast, AMN107 exhibited more potent effects in KIT D816V(-) HMC-1 cells. Corresponding results were obtained with Ba/F3 cells exhibiting wild-type or D816V-mutated KIT. The growth-inhibitory effects of PKC412 and AMN107 on HMC-1 cells were associated with induction of apoptosis and down-regulation of CD2 and CD63. PKC412 was found to cooperate with AMN107, imatinib, and cladribine (2CdA) in producing growth inhibition in HMC-1, but synergistic drug interactions were observed only in cells lacking KIT D816V. Together, PKC412 and AMN107 represent promising novel agents for targeted therapy of SM.
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http://dx.doi.org/10.1182/blood-2005-07-3022DOI Listing
January 2006

Hom s 4, an IgE-reactive autoantigen belonging to a new subfamily of calcium-binding proteins, can induce Th cell type 1-mediated autoreactivity.

J Immunol 2005 Jul;175(2):1286-94

Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.

Skin inflammation in atopic dermatitis starts with Th2 and IgE-mediated responses against exogenous allergens and, for unknown reasons, resembles features of a Th1-driven reaction in the chronic stages. We report the characterization of a human protein, Hom s 4, recognized by IgE autoantibodies from atopic dermatitis patients. The complete Hom s 4 cDNA codes for a 54-kDa basic protein containing two typical calcium-binding domains separated by an unusually long alpha-helical domain. Therefore, Hom s 4 and homologous proteins found by sequence comparison in mice, fruit flies, and nematodes constitute a novel subfamily of calcium-binding proteins. Using Hom s 4-specific Abs, it is demonstrated that the protein is strongly expressed within epidermal keratinocytes and dermal endothelial cells. Purified Hom s 4 showed IgE cross-reactivity with exogenous calcium-binding allergens from plants and fish but, in contrast to the exogenous allergens, induced only weak histamine release from patient basophils. However, the analysis of Hom s 4-specific cytokine and humoral immune responses indicated that Hom s 4 strongly induces Th1 responses which are accompanied by the release of IFN-gamma, a cytokine implicated in epithelial cell damage. Hom s 4-induced IFN-gamma production was found in normal individuals, in patients with chronic inflammatory skin diseases and in Th2-prone atopic persons, suggesting that Hom s 4 represents a protein with an intrinsic property to induce Th1-mediated autoreactivity. It may thus contribute to chronic skin inflammation in atopic as well as in nonatopic persons.
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http://dx.doi.org/10.4049/jimmunol.175.2.1286DOI Listing
July 2005

Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells.

FASEB J 2005 Jun 22;19(8):960-2. Epub 2005 Mar 22.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.

The mammalian target of rapamycin (mTOR) has recently been described to be constitutively activated in Bcr-Abl-transformed cells and to mediate rapamycin-induced inhibition of growth in respective cell lines. We have recently shown that rapamycin down-regulates expression of vascular endothelial growth factor (VEGF), a mediator of leukemia-associated angiogenesis, in primary CML cells. In the present study, we analyzed growth-inhibitory in vitro and in vivo effects of rapamycin on primary CML cells and asked whether rapamycin-induced suppression of VEGF in leukemic cells is related to growth inhibition. Rapamycin dose dependently inhibited growth of primary CML cells obtained from patients with imatinib-responsive or imatinib-resistant disease as well as growth of Bcr-Abl-transformed imatinib-resistant cell lines. Moreover, we observed potent cytoreductive effects of rapamycin in a patient with imatinib-resistant Bcr-Abl+ leukemia. The growth-inhibitory effects of rapamycin on CML cells were found to be associated with G1 cell cycle arrest and with induction of apoptosis. In all cell types tested, rapamycin was found to down-regulate expression of VEGF. However, exogenously added VEGF did not counteract the rapamycin-induced decrease in proliferation. In conclusion, rapamycin inhibits growth of CML cells in vitro and in vivo and, in addition, down-regulates expression of VEGF. Both effects may contribute to the antileukemic activity of the drug in CML.
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http://dx.doi.org/10.1096/fj.04-1973fjeDOI Listing
June 2005

Evaluation of normal and neoplastic human mast cells for expression of CD172a (SIRPalpha), CD47, and SHP-1.

J Leukoc Biol 2005 Jun 22;77(6):984-92. Epub 2005 Mar 22.

Department of Internal Medicine, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria.

Signal regulatory proteins (SIRPs) and tyrosine phosphatases have recently been implicated in the control of receptor tyrosine kinase (RTK)-dependent cell growth. In systemic mastocytosis (SM), neoplastic cells are driven by the RTK KIT, which is mutated at codon 816 in most patients. We examined expression of SIRPalpha, SIRPalpha ligand CD47, and Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), a tyrosine phosphatase-type, negative regulator of KIT-dependent signaling, in normal human lung mast cells (HLMC) and neoplastic MC obtained from nine patients with SM. As assessed by multicolor flow cytometry, normal LMC expressed SIRPalpha, CD47, and SHP-1. In patients with SM, MC also reacted with antibodies against SIRPalpha and CD47. By contrast, the levels of SHP-1 were low or undetectable in MC in most cases. Corresponding data were obtained from mRNA analysis. In fact, whereas SIRPalpha mRNA and CD47 mRNA were detected in all samples, the levels of SHP-1 mRNA varied among donors. To demonstrate adhesive functions for SIRPalpha and CD47 on neoplastic MC, an adhesion assay was applied using the MC leukemia cell line HMC-1, which was found to bind to immobilized extracellular domains of SIRPalpha1 (SIRPalpha1ex) and CD47 (CD47ex), and binding of these cells to CD47ex was inhibited by the CD172 antibody SE5A5. In summary, our data show that MC express functional SIRPalpha and CD47 in SM, whereas expression of SHP-1 varies among donors and is low compared with LMC. It is hypothesized that CD172 and CD47 contribute to MC clustering and that the "lack" of SHP-1 in MC may facilitate KIT-dependent signaling in a subgroup of patients.
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http://dx.doi.org/10.1189/jlb.0604349DOI Listing
June 2005

Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides.

Blood 2005 Apr 30;105(8):3303-11. Epub 2004 Dec 30.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, AKH-Wien, Waehringer Guertel 18-20, A-1097 Vienna, Austria.

Antiapoptotic members of the bcl-2 family have recently been implicated in the pathogenesis of chronic myeloid leukemia (CML), a hematopoietic neoplasm associated with the BCR/ABL oncogene. We have examined expression of MCL-1 in primary CML cells and BCR/ABL-transformed cell lines. Independent of the phase of disease, isolated primary CML cells expressed myeloid cell leukemia-1 (mcl-1) mRNA and the MCL-1 protein in a constitutive manner. The BCR/ABL inhibitor imatinib (=STI571) decreased the expression of MCL-1 in these cells. Correspondingly, BCR/ABL enhanced mcl-1 promoter activity, mcl-1 mRNA expression, and the MCL-1 protein in Ba/F3 cells. BCR/ABL-dependent expression of MCL-1 in Ba/F3 cells was counteracted by the mitogen-activated protein-kinase/extracellular signal-regulated kinase (MEK) inhibitor, PD98059, but not by the phosphoinositide 3-kinase inhibitor, LY294002. Identical results were obtained for constitutive expression of MCL-1 in primary CML cells and the CML-derived cell lines K562 and KU812. To investigate the role of MCL-1 as a survival-related target in CML cells, mcl-1 siRNA and mcl-1 antisense oligonucleotides (ASOs) were applied. The resulting down-regulation of MCL-1 was found to be associated with a substantial decrease in viability of K562 cells. Moreover, the mcl-1 ASO was found to synergize with imatinib in producing growth inhibition in these cells. Together, our data identify MCL-1 as a BCR/ABL-dependent survival factor and interesting target in CML.
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http://dx.doi.org/10.1182/blood-2004-02-0749DOI Listing
April 2005

CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens.

Am J Surg Pathol 2004 Oct;28(10):1319-25

Institute of Pathology, University of Tübingen, Tübingen, Germany.

The diagnosis of systemic mastocytosis (SM) is based primarily on the histologic and immunohistochemical evaluation of a bone marrow trephine biopsy specimen. Although mast cell (MC) specific antigens like tryptase and chymase are detectable in routinely processed tissue, no immunohistochemical markers that can be used to discriminate between normal and neoplastic MCs are yet available. We have investigated the diagnostic value of an antibody against CD25 for the immunohistochemical detection of MCs in bone marrow sections in 73 patients with SM and 75 control cases (reactive marrow, n = 54; myelogenous neoplasms, n = 21) and correlated the results with the presence of c-kit mutations. While MCs in almost all patients with SM (72 of 73) expressed CD25, none of the control samples contained CD25-positive MCs. Irrespective of the SM subtype, most of neoplastic MCs expressed CD25. In 3 patients with advanced MC disease, pure populations of neoplastic MCs were obtained and found to express CD25 mRNA by RT-PCR analysis. In addition, all patients with CD25-positive MCs contained c-kit mutations, while all control cases exhibited wild type c-kit. CD25 therefore appears to be a reliable immunohistochemical marker for the discrimination of neoplastic from normal/reactive MCs, with potential as a diagnostic tool in SM.
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http://dx.doi.org/10.1097/01.pas.0000138181.89743.7bDOI Listing
October 2004

Autoimmunity and atopic dermatitis.

Curr Opin Allergy Clin Immunol 2004 Oct;4(5):367-71

Department of Pathophysiology, Division of Immunopathology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.

Purpose Of Review: It has been demonstrated that a considerable percentage of patients suffering from atopic dermatitis mount IgE autoantibodies against a broad variety of human proteins. This review summarizes evidence for autoimmune mechanisms in atopic dermatitis and suggests novel pathomechanisms that may be involved in this disease.

Recent Findings: It has been shown that patients suffering from atopic dermatitis exhibit IgE autoreactivity to human proteins. These autoantigens are expressed in a variety of cell and tissue types. Complementary DNAs coding for IgE autoantigens have been identified, cloned and characterized at the molecular level. Using purified recombinant IgE autoantigens, it has been shown in paradigmatic models that IgE autoimmunity may be a pathogenetic mechanism in atopic dermatitis. Moreover, it has been shown that the levels of IgE autoantibodies are associated with severity of disease.

Summary: Patients suffering from severe manifestations of atopy mount IgE autoantibodies against a variety of human proteins. The levels of IgE autoantibodies correspond with disease severity. Several mechanisms of IgE autoimmunity may contribute to the pathogenesis of atopic dermatitis.
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http://dx.doi.org/10.1097/00130832-200410000-00007DOI Listing
October 2004