Bio

Honors & Awards


  • Fundamental Research Award, SFH French Society of Hematology - Valérie Meillet Prize (2012)
  • Fundamental Research Award, SFH French Society of Hematology - Laurette Fugain Prize (2011)
  • Travel Award, ASH American Society of Hematology 50th Annual Meeting (2008)
  • Travel Award, ISEH Society for Hematology and Stem Cells 37th Annual Scientific Meeting (2008)
  • Postdoctoral Research Fellowship, La Ligue Contre le Cancer (Respectfully declined this funding and accepted the one from ARC) (2005-2008)
  • Postdoctoral Research Fellowship, ARC Association pour la Recherche sur le Cancer - French Association for Cancer Research (2005-2008)
  • Best Poster Winner Award, School of Biological Sciences (2004)
  • International Cancer Technology Transfer Fellowship (ICRETT), UICC Union for International Cancer Control (2003)
  • Mobility Scholarship, SFH French Society of Hematology (2003)
  • Predoctoral Research Fellowship, La Ligue Contre le Cancer - French Union for Cancer Research (2001-2005)

Education & Certifications


  • Ph.D., University of Poitiers - France, Oncology (2005)
  • M.Sc., University of Poitiers - France, Molecular Biology (2001)
  • B.S., University of Poitiers - France, Biochemistry (2000)

Professional

Work Experience


  • Research Associate, Stanford University School of Medicine (USA), Contag Lab (10/1/2011 - Present)

    Location

    Stanford, CA, USA

  • Postdoctoral Fellow, Stanford University School of Medicine (USA), Contag Lab (1/1/2010 - 9/30/2011)

    - Demonstrated the effects of Heme Oxygenase-1 deletion in stress erythropoiesis
    - Determined the effects of the drug celastrol on hematopoietic subpopulations

    Location

    Stanford, CA, USA

  • Research Intern, University of Colorado Health Sciences Center (USA), Drabkin Lab (3/1/2003 - 8/31/2003)

    - Studied the role of the semaphorin SEMA3F in lung tumor development in vivo

    Location

    Denver, CO, USA

  • PhD candidate, University of Poitiers (France), Roche Lab (9/1/2001 - 7/5/2005)

    - Studied the regulation of the expression and the anti-tumoral functions of the semaphorin SEMA3F

    Location

    Poitiers, France

Publications

Journal Articles


  • Development of B Cells and Erythrocytes Is Specifically Impaired by the Drug Celastrol in Mice PLOS ONE Kusy, S., Ghosn, E. E., Herzenberg, L. A., Contag, C. H. 2012; 7 (4)

    Abstract

    Celastrol, an active compound extracted from the root of the Chinese medicine "Thunder of God Vine" (Tripterygium wilfordii), exhibits anticancer, antioxidant and anti-inflammatory activities, and interest in the therapeutic potential of celastrol is increasing. However, described side effects following treatment are significant and require investigation prior to initiating clinical trials. Here, we investigated the effects of celastrol on the adult murine hematopoietic system.Animals were treated daily with celastrol over a four-day period and peripheral blood, bone marrow, spleen, and peritoneal cavity were harvested for cell phenotyping. Treated mice showed specific impairment of the development of B cells and erythrocytes in all tested organs. In bone marrow, these alterations were accompanied by decreases in populations of common lymphoid progenitors (CLP), common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP).These results indicate that celastrol acts through regulators of adult hematopoiesis and could be used as a modulator of the hematopoietic system. These observations provide valuable information for further assessment prior to clinical trials.

    View details for DOI 10.1371/journal.pone.0035733

    View details for Web of Science ID 000305343200053

    View details for PubMedID 22545133

  • [TIF1? is a chief conductor of the hematopoietic system]. Médecine sciences : M/S Kusy, S., Roméo, P. 2011; 27 (8-9): 698-700

    View details for DOI 10.1051/medsci/2011278007

    View details for PubMedID 21880253

  • Heme Oxygenase-1 Deletion Affects Stress Erythropoiesis PLOS ONE Cao, Y., Kusy, S., Luong, R., Wong, R. J., Stevenson, D. K., Contag, C. H. 2011; 6 (5)

    Abstract

    Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-?. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-?; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

    View details for DOI 10.1371/journal.pone.0020634

    View details for Web of Science ID 000291097600112

    View details for PubMedID 21655188

  • Adult Hematopoiesis is Regulated by TIF1 gamma, a Repressor of TAL1 and PU.1 Transcriptional Activity CELL STEM CELL Kusy, S., Gault, N., Ferri, F., Lewandowski, D., Barroca, V., Jaracz-Ros, A., Losson, R., Romeo, P. 2011; 8 (4): 412-425

    Abstract

    Crosstalk between transcription factors and cytokines precisely regulates tissue homeostasis. Transcriptional intermediary factor 1? (TIF1?) regulates vertebrate hematopoietic development, can control transcription elongation, and is a component of the TGF-? signaling pathway. Here we show that deletion of TIF1? in adult hematopoiesis is compatible with life and long-term maintenance of essential blood cell lineages. However, loss of TIF1? results in deficient long-term hematopoietic stem cell (LT-HSC) transplantation activity, deficient short-term HSC (ST-HSC) bone marrow retention, and priming ST-HSCs to myelomonocytic lineage. These defects are hematopoietic cell-autonomous, and priming of TIF1?-deficient ST-HSCs can be partially rescued by wild-type hematopoietic cells. TIF1? can form complexes with TAL1 or PU.1-two essential DNA-binding proteins in hematopoiesis-occupy specific subsets of their DNA binding sites in vivo, and repress their transcriptional activity. These results suggest a regulation of adult hematopoiesis through TIF1?-mediated transcriptional repression of TAL1 and PU.1 target genes.

    View details for DOI 10.1016/j.stem.2011.02.005

    View details for Web of Science ID 000289707100013

    View details for PubMedID 21474105

  • How a suppressor of tumor gets hooked of the leukaemic proliferation in man M S-MEDECINE SCIENCES Pflumio, F., Kusy, S., Gerby, B., Romeo, P. 2011; 27 (2): 142-143

    View details for Web of Science ID 000292058000010

    View details for PubMedID 21382322

  • NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia JOURNAL OF EXPERIMENTAL MEDICINE Kusy, S., Gerby, B., Goardon, N., Gault, N., Ferri, F., Gerard, D., Armstrong, F., Ballerini, P., Cayuela, J., Baruchel, A., Pflumio, F., Romeo, P. 2010; 207 (10): 2141-2156

    Abstract

    TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1-expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1-LMO-Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-? (heterochromatin protein 1 ?) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.

    View details for DOI 10.1084/jem.20100745

    View details for Web of Science ID 000282649800011

    View details for PubMedID 20855495

  • Promoter characterization of Semaphorin SEMA3F, a tumor suppressor gene BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION Kusy, S., Potiron, V., Zeng, C., Franklin, W., Brambilla, E., Minna, J., Drabkin, H. A., Roche, J. 2005; 1730 (1): 66-76

    Abstract

    The tumor suppressor gene, Semaphorin SEMA3F, is frequently downregulated in lung cancer. Understanding the specific mechanism of SEMA3F suppression should be informative in terms of epithelial carcinogenesis and potential therapeutic interventions. Although a CpG-island is located 5083-3927 nt upstream of the translation start site, there have been no previous reports dealing with SEMA3F promoter regulation. We have now mapped the transcriptional initiation sites within the CpG-island and defined the region necessary for transcriptional activation. We then looked for evidence of SEMA3F promoter methylation since SEMA3F mutations are rare. By Southern blot and methylation-specific PCR assays, we identified a region in cell lines (i.e., area d at position minus 3850-3644 nt) for which methylation was significantly (P<0.0001) correlated with loss of expression. However, histone deacetylase inhibition with Trichostatin A was much more effective than 5-aza-2'-deoxycytidine in stimulating SEMA3F. Our results suggest that while SEMA3F promoter methylation correlates with repression, chromatin remodeling through histone deacetylase inhibition is sufficient to activate SEMA3F expression.

    View details for DOI 10.1016/j.bbaexp.2005.05.008

    View details for Web of Science ID 000231051100008

    View details for PubMedID 16005989

  • Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells NEOPLASIA Kusy, S., Nasarre, P., Chan, D., Potiron, V., Meyronet, D., Gemmill, R. M., Constantin, B., Drabkin, H. A., Roche, J. 2005; 7 (5): 457-465

    Abstract

    Loss of the 3p21.3-encoded semaphorins, SEMA3B and SEMA3F, is implicated in lung cancer development. Although both antagonize VEGF binding/response to neuropilin (NRP) receptors, in lung cancer lines, SEMA3F is predominantly expressed and preferentially utilizes NRP2. In lung cancer patients, SEMA3F loss correlates with advanced disease and increased VEGF binding to tumor cells. In cell lines, VEGF enhances adhesion and migration in an integrin-dependent manner, and exogenous SEMA3F causes cells to round and lose extracellular contacts. Using retroviral infections, we established stable SEMA3F transfectants in two NSCLC cell lines, NCI-H157 and NCI-H460. When orthotopically injected into nude rats, both control lines caused lethal tumors in all recipients. In contrast, all animals receiving H157-SEMA3F cells, survived to 100 days, whereas all H157 controls succumbed. In H460 cells, which express NRP1 but not NRP2, SEMA3F did not prolong survival. This antitumor effect in H157 cells was associated with loss of activated alpha(v)beta(3) integrin and adhesion to extracellular matrix components. In addition, H157-SEMA3F cells, and parental H157 cells exposed to SEMA3F-conditioned medium, showed loss of p42/p44 MAPK phosphorylation. Thus, in this in vivo lung cancer model, SEMA3F has potent antitumor effects, which may impinge on activated integrin and MAPK signaling.

    View details for DOI 10.1593/neo.04721

    View details for Web of Science ID 000229620100003

    View details for PubMedID 15967098

  • Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion NEOPLASIA Nasarre, P., Kusy, S., Constantin, B., Castellani, V., Drabkin, H. A., Bagnard, D., Roche, J. 2005; 7 (2): 180-189

    Abstract

    Previously, we demonstrated that loss of SEMA3F, a secreted semaphorin encoded in 3p21.3, is associated with higher stages in lung cancer and primary tumor cells studied with anti-vascular endothelial growth factor (VEGF) and SEMA3F antibodies. In vitro, SEMA3F inhibits cell spreading; this activity is opposed by VEGF. These results suggest that VEGF and SEMA3F compete for binding to their common neuropilin receptor. In the present report, we investigated the attractive/repulsive effects of SEMA3F on cell migration when cells were grown in a three-dimensional system and exposed to a SEMA3F gradient. In addition, we adapted the neurobiologic stripe assay to analyze the migration of tumor cells in response to SEMA3F. In the motile breast cancer cell line C100, which expresses both neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors, SEMA3F had a repulsive effect, which was blocked by anti-NRP2 antibody. In less motile MCF7 cells, which express only NRP1, SEMA3F inhibited cell contacts with loss of membrane-associated E-cadherin and beta-catenin without motility induction. Cell spreading and proliferation were reduced. These results support the concept that in a first step during tumorigenesis, normal tissues expressing SEMA3F would try to prevent tumor cells from spreading and attaching to the stroma for further implantation.

    View details for DOI 10.1593/neo.04481

    View details for Web of Science ID 000227413800010

    View details for PubMedID 15802023

  • p14(ARF),9p15(INK4b) and p16(INK4a) methylation status in chronic myelogenous leukemia LEUKEMIA & LYMPHOMA Kusy, S., Larsen, C. J., Roche, J. 2004; 45 (10): 1989-1994

    Abstract

    The INK4 family of proteins p15INK4b, p14ARF and p16INK4a function as cell cycle inhibitors where they are involved in the inhibition of G1 phase progression. Methylation of the p15INK4b promoter never seems to occur in solid tumors but is a major gene silencing mechanism in hematological malignancies. p14ARF and p16INK4a promoter methylation often occurs in solid tumors but also in leukemias and lymphomas. In chronic myelogenous leukemia (CML), only a few reports have been published regarding INK4 methylation and the results of the literature are discordant. Thus clearly, more works on large series have to be performed independently.

    View details for DOI 10.1080/10428190410001714025

    View details for Web of Science ID 000223523600004

    View details for PubMedID 15370242

  • Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas JOURNAL OF NEURO-ONCOLOGY Blanc, J. L., Wager, M., Guilhot, J., Kusy, S., Bataille, B., Chantereau, T., Lapierre, F., Larsen, C. J., Karayan-Tapon, L. 2004; 68 (3): 275-283

    Abstract

    In an effort to extend the potential relationship between the methylation status of MGMT promoter and response to CENU therapy, we examined the methylation status of MGMT promoter in 44 patients with glioblastomas. Tumor specimens were obtained during surgery before adjuvant treatment, frozen and stored at -80 degrees C until for DNA extraction process. DNA methylation patterns in the CpG island of the MGMT gene were determined in every tumor by methylation specific PCR (MSP). These results were then related to overall survival and response to alkylating agents using statistical analysis. Methylation of the MGMT promoter was detected in 68% of tumors, and 96.7% of methylated tumors exhibited also an unmethylated status. There was no relationship between the methylation status of the MGMT promoter and overall survival and response to alkylating agents. Our observations do not lead us to consider promoter methylation of MGMT gene as a prognostic factor of responsiveness to alkylating agents in glioblastomas.

    View details for Web of Science ID 000222346300012

    View details for PubMedID 15332332

  • Redundant functions but temporal and regional regulation of two alternatively spliced isoforms of Semaphorin 3F in the nervous system MOLECULAR AND CELLULAR NEUROSCIENCE Kusy, S., Funkelstein, L., Bourgais, D., Drabkin, H., Rougon, G., Roche, J., Castellani, V. 2003; 24 (2): 409-418

    Abstract

    SEMA3F is a secreted semaphorin that affects axon and cell guidance in the developing nervous system, and is also thought to have anti-tumor activity. Two spliced forms of SEMA3F have been identified that differ by the insertion of 31 amino acids in the sema domain. Here, we investigated the bioactivity of these isoforms and show, using coculture and binding assays, that they share common axonal chemorepulsive properties and binding to neuropilin receptors. SEMA3F isoforms were also found to regulate endothelial cell morphology by remodeling lamellipodial protrusions. Although Sema3F expression globally decreased during mouse development, we noted an enrichment of the longest isoform at postnatal stages in some territories such as the brainstem and spinal cord. These results indicate that although functionally redundant in cell culture assays, Sema3F spliced forms are characterized in vivo by a temporal and regional specific regulation during maturation of the nervous system.

    View details for DOI 10.1016/S1044-7431(03)00197-0

    View details for Web of Science ID 000186164400012

    View details for PubMedID 14572462

  • WNT7a induces E-cadherin in lung cancer cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ohira, T., Gemmill, R. M., Ferguson, K., Kusy, S., Roche, J., Brambilla, E., Zeng, C., Baron, A., Bemis, L., Erickson, P., Wilder, E., Rustgi, A., Kitajewski, J., Gabrielson, E., Bremnes, R., Franklin, W., Drabkin, H. A. 2003; 100 (18): 10429-10434

    Abstract

    E-cadherin loss in cancer is associated with de-differentiation, invasion, and metastasis. Drosophila DE-cadherin is regulated by Wnt/beta-catenin signaling, although this has not been demonstrated in mammalian cells. We previously reported that expression of WNT7a, encoded on 3p25, was frequently downregulated in lung cancer, and that loss of E-cadherin or beta-catenin was a poor prognostic feature. Here we show that WNT7a both activates E-cadherin expression via a beta-catenin specific mechanism in lung cancer cells and is involved in a positive feedback loop. Li+, a GSK3 beta inhibitor, led to E-cadherin induction in an inositol-independent manner. Similarly, exposure to mWNT7a specifically induced free beta-catenin and E-cadherin. Among known transcriptional suppressors of E-cadherin, ZEB1 was uniquely correlated with E-cadherin loss in lung cancer cell lines, and its inhibition by RNA interference resulted in E-cadherin induction. Pharmacologic reversal of E-cadherin and WNT7a losses was achieved with Li+, histone deacetylase inhibition, or in some cases only with combined inhibitors. Our findings provide support that E-cadherin induction by WNT/beta-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and that loss of WNT7a expression may be important in lung cancer development or progression by its effects on E-cadherin.

    View details for DOI 10.1073/pnas.1734137100

    View details for Web of Science ID 000185119300054

    View details for PubMedID 12937339

  • p14(,)(ARF) p15(INK4b), and p16(INK4a) methylation status in chronic myelogenous leukemia BLOOD Kusy, S., Cividin, M., Sorel, N., Brizard, F., Guilhot, F., Brizard, A., Larsen, C., Roche, J. 2003; 101 (1): 374-375

    View details for Web of Science ID 000180142500064

    View details for PubMedID 12485942

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