Izidore S. Lossos, M.D.
Professor of Clinical Medicine
Description of Research
Dr. Lossos’ laboratory research focuses on studies of lymphoma, with major interest in understanding the mechanisms of lymphoma pathogenesis, identification of aberrant signaling pathways, identification of novel genes that may have a unique role in this disease, construction of molecular prognostic models that will allow identification of patients that will respond to therapy, and studies of novel therapeutic agents.
Examples of ongoing projects:
miRNAs: miRNAs are short non translated RNAs that regulate expression of different RNAs and proteins. Recent work in the laboratory (Blood 2009) demonstrated distinct expression of miRNA at distinct differentiation stages of B cell differentiation and in different types of lymphoma. Dr. Lossos' recent work identified several miRNAs that harbor prognostic significance in diffuse large B-cell lymphoma (DLBCL). His current studies focus on identification of specific targets of these distinct miRNAs, their pathogenetic role in DLBCL and mechanisms of regulation (e.g. epigenetic regulation).
HGAL Function: Dr. Lossos has cloned the human germinal center-associated lymphoma (HGAL) gene. This is a germinal center-specific cytoplasmic protein which is involved in cell signaling. Expression of this gene correlates with better outcome of patients with DLBCL and Hodgkin lymphoma. Recently his team has identified that HGAL regulates cell motility by interaction with actin, myosin (Blood 2008), and regulating cytoskeleton by activation of RhoA signaling pathway (in press). His preliminary studies demonstrate that this protein also regulates additional B cell functions (eg. BCR signaling). Further studies to identify HGAL functions in normal B cells and its role in lymphoma pathogenesis are in progress. In addition, Dr. Lossos’ laboratory is investigating mechanisms of HGAL expression regulation.
LMO2 function: Previous studies in Dr. Lossos’ laboratory led to identification of a 6 gene model for prediction of outcome of patients with diffuse large B-cell lymphoma. Currently, this model is validated in an ongoing NIH funded prospective study conducyed by Dr. Lossos' laboratory. In addition, they focus on elucidation of the function of these 6 genes. One of these genes with the best predictive power is LMO2, in which high expression correlates with improved outcome. LMO2 is transcriptional factor, involved in leukemia formation, but its role in B cell physiology and B cell lymphomagenesis is unknown. Ongoing studies in the laboratory demonstrated novel functions of LMO2 in these conditions.
IL-21: IL-21 is a cytokine involved in regulation of different immune cells. Recent work in the laboratory (Blood 2010) demonstrated that IL-21 is effective in inducing cell death of DLBCL in vitro and tumor regression in vivo. Mechanism of the unique IL-21 effects on apoptosis of DLBCL was identified. Current studies focus on identification of the possible resistance mechanisms, generation of fusokine of IL-21 with rituximab to improve its potency and initiation of translational clinical trial in DLBCL patients.
Kinases: Using a novel mass spect-based approach, Dr. Lossos' laboratory has performed a global kinase activity assay in DLBCL. This led to identification of novel signalizing pathways activated in DLBCL compared to normal B cells. Initial studies focusing on one of these pathways demonstrated that inhibition of this pathway leads to lymphoma cell death. Small molecule targeting this pathway was synthesized and is currently evaluated in I vitro and in vivo studies. Further signaling pathways will be examined as well.
Additional studies in other types of lymphoma (e.g. primary effusion lymphoma, PNAS 2010) are also ongoing. Overall, Dr. Lossos and his laboratory are well funded and very active with more than 60 publications in the last five years.
Selected Cancer-Related Publications
- Dagan LN, Jiang X, Bhatt S, Cubedo E, Rajewsky K, Lossos IS. miR-155 regulates HGAL expression and increases lymphoma cell motility. Blood 119:513-20, 2012. Read more »
- Azambuja D, Natkunam Y, Biasoli I, Lossos IS, Anderson MW, Morais JC, Spector N. Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin's lymphoma. Ann Oncol 23:736-42, 2012. Read more »
- Hosein PJ, Craig MD, Tallman MS, Boccia RV, Hamilton BL, Lewis JJ, Lossos IS. A multicenter phase II study of darinaparsin in relapsed or refractory Hodgkin's and non-Hodgkin's lymphoma. Am J Hematol 87:111-4, 2012. Read more »
- Morgensztern D, Walker GR, Koniaris LG, Lossos IS. Lack of survival improvement in patients with peripheral T-cell lymphoma: a Surveillance,Epidemiology,and End Results analysis. Leuk Lymphoma 52:194-204, 2011. Read more »
- Ramos JC, Lossos IS. Newly emerging therapies targeting viral-related lymphomas. Curr Oncol Rep 13:416-26, 2011. Read more »
- Bayraktar S, Bayraktar UD, Stefanovic A, Lossos IS. Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients. Br J Haematol 152:72-80, 2011. Read more »
- Bayraktar S, Bayraktar UD, Ramos JC, Stefanovic A, Lossos IS. Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors. J Neurooncol 101:257-65, 2011. Read more »
- Alencar A, Pitcher D, Byrne G, Lossos IS. Primary bone lymphoma--the University of Miami experience. Leuk Lymphoma 51:39-49, 2010. Read more »
- Alizadeh AA, Bohen SP, Lossos C, Martinez-Climent JA, Ramos JC, Cubedo-Gil E, Harrington WJ, Lossos IS. Expression profiles of adult T-cell leukemia-lymphoma and associations with clinical responses to zidovudine and interferon alpha. Leuk Lymphoma 51:1200-16, 2010. Read more »
- Sarosiek KA, Cavallin LE, Bhatt S, Toomey NL, Natkunam Y, Blasini W, Gentles AJ, Ramos JC, Mesri EA, Lossos IS. Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma. Proc Natl Acad Sci U S A 107:13069-74, 2010. Read more »
- Gratzinger D, Advani R, Zhao S, Talreja N, Tibshirani RJ, Shyam R, Horning S, Sehn LH, Farinha P, Briones J, Lossos IS, Gascoyne RD, Natkunam Y. Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R-CHOP). Br J Haematol 148:235-44, 2010. Read more »
- Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide,vincristine, ifosfamide, etoposide, cytarabin, and thalidomide (R-MACLO-IVAM-T),a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma 51:406-14, 2010. Read more »
- Sarosiek KA, Malumbres R, Nechushtan H, Gentles AJ, Avisar E, Lossos IS. Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas. Blood 115:570-80, 2010. Read more »
- Malumbres R, Sarosiek KA, Cubedo E, Ruiz JW, Jiang X, Gascoyne RD, Tibshirani R, Lossos IS. Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood 113:3754-64, 2009. Read more »
- Stefanovic A, Lossos IS. Response: Variability in the prevalence of Chlamydophila psittaci infection in patients with OAML. Blood 114:3499-500,2009. Read more »
- Stefanovic A, Lossos IS. Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114:501-10, 2009. Read more »
- Habermann TM, Lossos IS, Justice G, Vose JM, Wiernik PH, McBride K, Wride K, Ervin-Haynes A, Takeshita K, Pietronigro D, Zeldis JB, Tuscano JM. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 145:344-9, 2009. Read more »
- Gratzinger D, Zhao S, West R, Rouse RV, Vogel H, Gil EC, Levy R, Lossos IS, Natkunam Y. The transcription factor LMO2 is a robust marker of vascular endothelium and vascular neoplasms and selected other entities. Am J Clin Pathol 131:264-78, 2009. Read more »
- Han HS, Escalón MP, Hsiao B, Serafini A, Lossos IS. High incidence of false-positive PET scans in patients with aggressive non-Hodgkin's lymphoma treated with rituximab-containing regimens. Ann Oncol 20:309-18, 2009. Read more »
- Alencar AJ, Bustinza E, Barker J, Byrne GE, Lossos IS. Hematodermic tumor presenting with generalized skin involvement. J Clin Oncol 27:3059-61, 2009. Read more »
- Alizadeh AA, Gentles AJ, Lossos IS, Levy R. Molecular outcome prediction in diffuse large-B-cell lymphoma. N Engl J Med 360:2794-5, 2009. Read more »
- Kalkanis D, Stefanovic A, Paes F, Escalon MP, Serafini A, Lossos IS. [18F]-fluorodeoxyglucose positron emission tomography combined with computed tomography detection of asymptomatic late pulmonary toxicity in patients with non-Hodgkin lymphoma treated with rituximab-containing chemotherapy. Leuk Lymphoma 50:904-11, 2009. Read more »
Collaborating in the Multidisciplinary Research Program(s):