The role of cIAP1 and cIAP2 in chronic lymphocytic leukemia

Signals derived from the microenvironment have a demonstrated pathophysiological relevance in the establishment, progression and chemoresistance of chronic lymphocytic leukemia (CLL). Among these, B-cell receptor (BCR)-, BAFF (B-cell activating factor)-, APRIL (a proliferating ligand)-, and CD40/CD40L- mediated signals, all transmitted via the NF<U+03BA>B pathway, have been shown to impact CLL development. Recently, mutations within BIRC3, encoding the NF<U+03BA>B pathway regulator cIAP2 (cellular inhibitor of apoptosis 2), were shown to be associated with poor clinical outcome and chemoresistance to Fludarabine (Rossi et. al. Blood 2012), the backbone of current therapy regimens. We thus hypothesized that the rare BIRC3 mutations indicated a critical pathway in CLL biology. BIRC3/cIAP2, together with its close homologue BIRC2/cIAP1, is a central regulator of the non- canonical NF<U+03BA>B pathway. This alternate NF<U+03BA>B signalling pathway is particularly predominant in lymphocytes. In B-cells, non-canonical NF<U+03BA>B signalling is mediated via a very specific subset of receptors including BAFF-R and CD40, and largely impacts B cell survival, maturation, differentiation, and germinal center (GC) formation. Given these observations, the overall goal of the proposed study is to characterize the contribution of cIAP1 and 2 to CLL pathophysiology and chemoresistance. We will achieve this by: (1) investigating the impact of cIAP1 and cIAP2 deficiency on clinical progression and CLL development by correlating expression levels with clinical features of CLL, (2) define the upstream signals and molecular mechanisms that regulate protein expression, focusing on known microenvironmental cues (3) analyse the downstream consequences of cIAP1/2 dysregulation on CLL viability and proliferation, and (4) characterize the molecular connection between cIAP deficiency and p53 dysfunction that contributes to Fludarabine chemoresistance. As CLL displays such an intricate dependence on its microenvironment, both complex in vitro co-culture systems using primary human samples as well as animal models will be employed in order to sufficiently recreate the multifaceted microenvironmental cues required, while retaining important information on human CLL behavior.

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