student profile: Mr Yandong Shen


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Thesis work

Thesis title: Hypoxic Microenvironment in Chronic Lymphocytic Leukemia and Novel Treatment Strategies

Supervisors: Richard CHRISTOPHERSON , Stephen MULLIGAN

Thesis abstract:

Background: The importance of the tumour microenvironment in the pathogenesis of chronic lymphocytic leukemia (CLL) is becoming increasingly apparent. The interaction of CLL cells with T-cells and the stroma within proliferation centres promotes survival, proliferation and induces immunophenotypic changes on the surface of the CLL cells. Defining the immunophenotype of CLL cells derived from the tumour microenvironment may identify novel markers of progressive disease and therapeutic targets.�br /� �br /� Methods: The interaction of CLL cells with T-cells and the stroma of proliferation centres within lymph nodes was mimicked by co-culturing primary CLL cells with human CD40L (sCD154)-expressing mouse fibroblasts. The DotScanTM cluster of differentiation (CD) antibody microarray was used to screen for changes in the expression of a panel of 184 CD antigens. The effects of idelalisib and ibrutinib were studied using flow cytometry on a panel of 7 of the 184 antigens selected from our analysis of CLL cells co-cultured with CD40L-fibroblasts.�br /� �br /� Results: We identified 18 CD antigens that were significantly altered in expression following co-culture of CLL cells with CD40L-expressing fibroblasts (CD24, CD25, CD27, CD40, CD53, CD58, CD62L, CD69, CD80, CD81, CD83, CD84, CD95, CD98, CD126, CD150, CD166, and CD229). Although the effects of ibrutinib and idelalisib treatment were variable between CLL patient samples both drugs countered the CD40L fibroblast-induced changes in expression of CD24, CD53, CD62L, CD80, CD95, CD126 and CD150.�br /� �br /� Conclusions: Since CLL progression and drug resistance depend on the interaction of CLL cells with the tumour microenvironment, the changes in CD antigen expression identified here provide a better understanding of the mechanisms underlying this interaction. The antigens identified using the unique DotScanTM CD antibody microarray technology may be used as markers of progressive disease and as therapeutic targets. Our data also provide novel information concerning the mechanisms by which ibrutinib and idelalisib lead to the liberation of CLL cells from the lymph nodes and bone marrow.

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