Characterization of signaling pathways in B-lymphoma cells at the single cell level
Characterization of signaling pathways in B-cell lymphoma
Lymphoma is a solid cancer of lymphocytes in lymph nodes. Many different groups of lymphoma exist, but even patients with same diagnoses can have variable clinical course. We used flow cytometry analysis to identify signaling profiles of lymphoma cells and infiltrating immune cells that correlated with patient's outcome and response to therapy.
During my stay at in Dr. Levy's lab, Stanford University 2008 – 2009, the main focus was to use high-throughput flow cytometry analysis to predict response to therapy and to indentify tumor heterogeneity in B cell lymphoma. The patient samples were obtained from Stanford Hospital, CA, and the Norwegian Radium Hospital, and included follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). All cases had long time follow-up. We stimulated the patient samples with various stimulation conditions, including cytokines like IL-4, IL-7, and IL-21, all known to have important effects in normal B or T cells, in addition to activation of the B cell antigen receptor (BCR). We then used flow cytometry to study induced signaling at the single cell level. We discovered that FL patients that did not respond to chemotherapy treatment and lived for only a short time, had a large fraction of their cancer cells unresponsive to BCR, in contrast to long lived patients in which the majority of the cancer cells did respond, similar to the response seen in normal B cells. We termed this subset negative prognostic lymphoma (LNP; Irish et al, submitted). The LNP subset increased over time and was related to therapy resistance. We have also found the LNP subset present in other lymphoma entities, including MCL and CLL, but as these projects are still ongoing, we don't know whether the subset size has prognostic impact also in these malignancies.
During my stay in US, I was also involved in projects studying immunomodulatory therapies; including antibodies that could stimulate T effector cell and NK-mediated tumor cell killing in vivo (i.e. CD137 ab therapy, Houot et al). Another antibody which target CD47, was also shown to have anti-tumor activity through stimulation of phagocytosis, and had synergistic effect when combined with anti-CD20 therapy (Chao et al, submitted). Furthermore, a study where a gene module approach was used to analyze various FL gene expression data sets, revealed that a pluripotency signature predicted histological transformation and were associated with an adverse prognosis in FL (Gentles et al).
Characterization of signaling pathways in B-lymphoma cells
The aim is to identify changes in intracellular signaling pathways in the tumor cells or in the normal T cells, present in the patient sample at diagnosis that can stratify poutcome and response to therapy
Jeg fikk overført de tildelte Helse Sør/Øst midlene for 2008 til 2009, og har således ikke begynt å bruke av midlene enda. Prosjektet ble immidlertid startet opp mars 2008, men med midler fra Rikshospitalet HF. Prosjektet vil bli sluttført i august 2009 med Helse Sør/Øst midlene.
Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion.
Blood 2009 Oct;114(16):3431-8. Epub 2009 jul 29
A pluripotency signature predicts histologic transformation and influences survival in follicular lymphoma patients.
Blood 2009 Oct;114(15):3158-66. Epub 2009 jul 27
June H. Myklebust: Prognostic impact of impaired signaling in lymphoma tumor cells and infiltrating T cells in follicular lymph
Foredrag, Onkologisk Forum, 19.nov 2009, Oslo
Signaling profiles of lymphoma patient samples by flow cytometry
Foredrag, BD FACS usermeeting, 5.nov 2009, Oslo
A subpopulation of follicular lymphoma tumor infiltrating T cells shows suppressed common gamma chain cytokine signaling
Selected as oral presentation, ASH 2009, New Orleans
Use of flowcytometry to explore signaling in lymphoma B cells and tumor infiltrating T cells from patients with Diffuse large B
Stanford Oncology and Hematology Annual Research Retreat 2008
Signaling Profiles of Cancer Cell
American Society of Hematology Annual meeting 2008