Study Pro-Oncogenic Role of BCL6 in CLL Tumorigenesis

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PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is an adult B-cell malignancy accounting for about a third of leukemia diagnoses in the US. While B-cell receptor (BCR)-signal-inhibitors are changing the management of CLL, these are not curative and resistance can develop; often leading to more aggressive disease. Given this, understanding the molecular events driving CLL oncogenesis and therapeutic resistance warrants in-depth investigation. CLL shows remarkable clinical heterogeneity, with some patients pursuing an indolent course, while others progress rapidly and require early treatment. Extensive heterogeneity exists also at the genetic, epigenetic, and transcriptional level. In addition to constitutively active BCR signal, we previously reported the existence of a highly active receptor tyrosine kinase (RTK) AXL in CLL cells regulating multiple signal mediators including LYN, PI3K/AKT and PLCγ2 thus, potentiating CLL cell survival signals. B-cell lymphoma 6 (BCL6) is a transcriptional repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms, regulating numerous genes involved in DNA damage and cell proliferation. Most recently, we have detected expression of BCL6 in CLL cells from previously untreated CLL patients both at mRNA and protein levels. Our preliminary findings indicate that HSP90 overexpression may regulate BCL6 protein levels in CLL cells. Importantly, our initial data also suggest that aberrant expression of BCL6 may regulate the highly active AXL survival signal in CLL cells. However, the mechanism of aberrant upregulation of BCL6 in CLL cells, and its precise functional contributions to CLL biology and disease pathogenesis are poorly understood. It is also not clear if the target transcriptional landscape of aberrantly expressed BCL6 in CLL cells is different than that is detected in normal germinal center B-cells. Therefore, the central hypothesis of this application is that overexpression of BCL6 in CLL cells represents highly aggressive disease with shorter time to therapy. We also postulate that BCL6 upregulation potentiates CLL cell survival signals and resistance to BCR-targeted agents. We propose – Aim 1: Evaluate if BCL6 upregulation in CLL cells drives disease progression; Aim 2: Define the mechanism of BCL6 upregulation and its role in CLL cell biology and signaling. The proposed in-depth studies will assess if “high BCL6” level in CLL cells serves as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of BCL6 aberrant expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies have great potential to establish a new prognostic parameter and therapeutic avenue via targeting BCL6 in CLL cells in combination with the current BCR-targeted therapy, ibrutinib.