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Low Bone Marrow Oxygen Tension and Hypoxia-Inducible Factor-1&Alpha Letters to the Editor 1967 collected and the concentration of TNF-a and IL-12p70 was work was supported by grants from the Deutsche Forschungsge- analyzed. As depicted in Table 1, 8 of 10 primary AML cell meinschaft to MB and GE (SFB655, project B2 and B7) and from samples did not alter the secretion of TNF-a and IL-12 by the Medical Faculty, Technical University of Dresden to RW. activated slanDCs. Interestingly, two AML cell samples sig- R Wehner1, P Schumacher1, M Bornha¨user2, nificantly impair the capability of activated slanDCs to produce 2 3 1 1 these cytokines. The evaluated AML cell samples did not secrete G Ehninger , K Scha¨kel , M Bachmann and M Schmitz 1Institute of Immunology, Medical Faculty, Technical a TNF- and IL-12 under these conditions as determined by flow University of Dresden, Dresden, Germany; cytometry (data not shown). 2Department of Medicine I, University Hospital of Dresden, In summary, we showed that none of the 10 evaluated AML Dresden, Germany and cell samples induces the secretion of the cytotoxic effector 3Department of Dermatology, University Hospital of molecule TNF-a or the immunomodulatory cytokine IL-12 in Heidelberg, Heidelberg, Germany unstimulated slanDCs. The failure to trigger slanDC activation E-mail: [email protected] efficiently can be explained by an insufficient expression of ‘danger’ molecules by AML cells and/or the production of References inhibitory molecules. As a consequence, the capacity 7 of slanDCs to mediate tumor-directed cytotoxicity and to 1 Barrett AJ, Le Blanc K. Immunotherapy prospects for acute myeloid 8 6 activate tumor-reactive NK cells and T cells may be impaired. leukaemia. Clin Exp Immunol 2010; 161: 223–232. In addition, we found that two AML cell samples significantly 2 Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini inhibit TNF-a and IL-12 secretion by activated slanDCs. MTL et al. Loss of mismatched HLA in leukemia after stem cell Besides the potential of primary AML cells to evade the transplantation. N Engl J Med 2009; 361: 478–488. control of NK cells and T cells,2–4 their failure to trigger 3 Baessler T, Krusch M, Schmiedel BJ, Kloss M, Baltz KM, Wacker A et al. Glucocorticoid-induced tumor necrosis factor receptor-related unstimulated native human DCs as well as their capability to protein ligand subverts immunosurveillance of acute myeloid inhibit the cytokine production of activated DCs may represent leukemia in humans. Cancer Res 2009; 69: 1037–1045. additional immune escape mechanisms. These various mechan- 4 Baessler T, Charton JE, Schmiedel BJ, Gru¨nebach F, Krusch M, isms may be important in the development and relapse Wacker A et al. CD137 ligand mediates opposite effects in human of AML despite immunosurveillance. In addition, they may and mouse NK cells and impairs NK cell reactivity against human also have implications for the design of immunotherapeutic acute myeloid leukemia in humans. Blood 2010; 115: 3058–3069. 5 Scha¨kel K, Kannagi R, Kniep B, Goto Y, Mitsuoka C, Zwirner J et al. strategies for AML. 6-Sulfo LacNAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type of human dendritic cells. Immunity 2002; 17: 289–301. Conflict of interest 6 Scha¨kel K, von Kietzell M, Ha¨nsel A, Ebling A, Schulze L, Haase M et al. Human 6-sulfo LacNAc-expressing dendritic cells are principal producers of early interleukin-12 and are strictly The authors declare no conflict of interest. controlled by contact with erythrocytes. Immunity 2006; 24: 767–777. 7 Schmitz M, Zhao S, Deuse Y, Scha¨kel K, Wehner R, Wo¨hner H et al. Acknowledgements Tumoricidal potential of native blood dendritic cells: direct tumor cell killing and activation of NK cell-mediated cytotoxicity. J Immunol 2005; 174: 4127–4134. The technical assistance of Ba¨rbel Lo¨bel, Karin Gu¨nther, Jule 8 Wehner R, Lo¨bel B, Bornha¨user M, Scha¨kel K, Cartellieri M, Kriegel and Anne Seltmann (all from the Institute of Immunology) Bachmann M et al. Reciprocal activating interaction between is greatly appreciated. We also thank Silke Soucek and Michael 6-sulfo LacNAc+ dendritic cells and NK cells. Int J Cancer 2009; Kramer for providing the characteristics of the AML cells. This 124: 358–366. Low bone marrow oxygen tension and hypoxia-inducible factor-1a overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138þ cells Leukemia (2010) 24, 1967–1970; doi:10.1038/leu.2010.193; In this study, we investigated BM oxygen partial pressure published online 2 September 2010 (pO2) and saturation (sO2) by aspiration of 2 ml of marrow samples immediately analyzed by a gas analyzer (ABL800 FLEX Radiometer, Copenhagen, Denmark) in a cohort of 44 Multiple myeloma (MM) is characterized by an increase of bone patients, including symptomatic MM (n ¼ 25), smoldering MM marrow (BM) angiogenesis that occurs in close contact with (n ¼ 8) and Monoclonal Gammopathy of Undetermined plasma cells accumulation.1,2 Hypoxia is associated to angio- Significance (n ¼ 11). Six healthy subjects without any genesis in solid tumors and hypoxia-inducible factor (HIF)-1a is pathological BM involvement were also investigated. Protocol a critical trigger and regulator of the angiogenic switch.3,4 It is was approved by our local ethic committee. We show that known that the BM microenvironment is hypoxic in healthy BM of MM patients was hypoxic, even if any significant 5 subjects, however, the BM oxygen levels in patients with MM difference in both pO2 and sO2 was not observed in comparison have never been investigated and the effects of hypoxia and its with smoldering MM patients, Monocolonal Gammopathy of main transcription factor HIF-1a on the transcriptional and Undetermined Significane or healthy subjects, and in relation- proangiogenic profiles of CD138 þ cells are not known. ship with the stage of MM disease (P ¼ 0.6; Figure 1a). Leukemia Letters to the Editor 1968 Figure 1 Oxygen partial pressure and saturation, hypoxia-inducible factor-1a (HIF-1a) protein stabilization in the bone marrow of multiple myeloma (MM) patients: Role of HIF-1a on the production of the proangiogenic molecules and properties of MM cells. (a) The partial pressure of oxygen (pO2)and saturation (sO2) into the bone marrow was evaluated in a cohort of MM patients, smoldering MM, Monoclonal Gammopathy of Undetermined Significance and healthy subjects. Bone marrow was aspirated into a blood gas syringe and analyzed immediately. Graphs represent the average±s.d. of bone marrow pO2 and sO2. (b)HIF-1a protein stabilization was evaluated by immunohistochemistry in fixed bone biopsies obtained from multiple myeloma patients. i: negative control; ii–iv:HIF-1a protein immunostaining in myeloma cells of three representative patients; v positive control (lung adenocarcinoma). (c) Endothelial-like cells were stimulated with the conditioned media (dilution 1:2) of JJN3 cells previously transfected with a non- specific control siRNA (Cy) or anti-HIF-1a small interfering RNA (siRNA) and incubated under normoxic or hypoxic conditions. Graphs represent the mean±s.d. values of the number of capillary junction, tubules and the tubule length, respectively of two independent experiments tested twice (Control ¼ D-MEM medium not conditioned by JJN3; *Po0.05). Leukemia Letters to the Editor 1969 Accordingly, we did not find any significant difference in the Table 1 Main genes induced by hypoxia and regulated by HIF-1a messenger RNA (mRNA) expression of HIF-1a target genes in MM cells (AK3 and BNIP3) in CD138 þ samples from Monocolonal Gammopathy of Undetermined Significane and MM cases (i) Main genes induced by (ii) Genes regulated by + (data not shown) similar to what was previously observed for hypoxia in purified CD138 cells HIF-1a cells in JJN3 the expression of VEGFA mRNA in MM cells by others.6,7 Oxidative stress signaling HIF-1a regulating genes The median pO2 and sO2 values measured in MM BM HMOX1 EGLN3, EGLN1 samples of our cohort of patients and controls were analogous GCLC HIF-1a target genes to those reported in healthy volunteers.5 However, in an MM FTH1 AK3L1, BNIP3 L, HIG2 mouse model, it has been recently reported that both normal TXN Hypoxia signaling and MM-infiltrated BM are hypoxic, although the level of TXRND1 UBE2J1, P4HB, EP300 NQO1 Oxidative stress signaling hypoxia was lower in MM BM.8 The discrepancy between our NQO2 SOD2, PTGS2,TXN data and those obtained in mice could be due in part to the Hypoxia signaling Glycogenolysis regulating genes 8 different method used by Asosingh et al. in the detection of UBE2H ENO2, ALDOC, PFKFB3, HK2, hypoxia, based on pimonidazole hypoxyprobe binding, but also HSP90AA1 PDK1, PFKFB4 to the lower physiological oxygen tension reported in mice8,9 as HSP90AB1 Pro-angiogenic genes compared to human BM microenvironment.5 Protein ubiquitination pathway VEGFA, VEGFB, TGFB1, PGF XIAP Transcription factors Next, we evaluated how hypoxic treatment with the hypoxic USP47 MAF, IRF4, JUN, NFKB2 mimetic drug CoCl2 at 100 mM (Sigma Aldrich, St Louis, USP42 IL-6 and IGF-1 Signaling þ MO, USA) modified the transcriptional profile of CD138 cells UBR2 IL6ST, IGFBP3 isolated form MM patients by U133 Plus2.0 Arrays GeneChip UBC Cell cycling genes (Affymetrix, Santa Clara, CA, USA). By supervised analysis MDM2 CDKN1C (p57), CCNG2, CDK6, Pro-angiogenic genes performed on 11 paired MM samples we observed that hypoxia CCNA2, CKS2 þ VEGFA p53 signaling significantly modulated 714 genes in CD138 cells isolated IL-8 TP73, HIPK2 from MM patients. Interestingly, genes belonging either to HIF-1a, VEGF and IL-8 signaling Chemokines and chemokine oxidative stress and hypoxia signaling, including heme oxyge- PIK3C2A receptors nase 1 (HMOX1) and the heat-shock protein 90 kDa alpha MDM2 CXCR4, CCL5 (HSP90AA1; HSP90AB1), or to protein ubiquitination pathway, Protein transport Adhesion molecules TNPO1 ICAM1, CADM1 such as XIAP, were significantly upregulated by hypoxia.
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