Project Outline:

Targeting NIK in haematological malignancies

The NF-kB pathway plays a crucial role in B cell homeostasis and function.  Transcriptional activity of NF-kB is mediated by a number of homo and hetero-dimeric complexes containing p50 (NF-kB1) or p52 (NF-kB2). The rate limiting step in the canonical pathway is the degradation of inhibitor of kappa-B alpha (IkBa) which under steady state condition holds p50 containing complexes in the cytoplasm.  In contrast, the non-canonical NF-kB pathway is driven by NIK (Map3k14) dependent processing of p100 to p52 resulting in translocation of dimer complexes containing p52 to enter the nucleus and drive transcription. Despite a number of high profile publications describing a non-redundant role for NF-kB in a number of B cell malignancies, efforts so far in targeting the canonical pathway have failed possibly because of an ongoing requirement of this pathway in a number of organs. Studies done so far on the non-canonical pathway indicate that this pathway is required for the development of stroma in primary and secondary lymphoid organs but less important for the homeostasis of mature immune cells. The non-canonical pathway is aberrantly activated in a number of haematological malignancies as described below.

Multiple Myeloma (MM):

Multiple myeloma (MM) is a chronic and incurable plasma cell malignancy.  Despite immense heterogeneity in clinical presentation and genetic events that determine outcome, a common feature of all MM is aberrant activation of NF-kB. Most myeloma patient samples and cell lines have activation of the canonical and/or the alternate pathway. Mutations in upstream regulators of the non-canonical pathway like TRAF3, TRAF2, cIAP1/2 (BIRC2/3) resulting in constitutive activation of NIK are common in MM.

Diffuse Large B Cell Lymphoma (DLBCL):

DLBCL, one of the most common types of B-cell lymphoma with two main subtypes based on cell of origin classification: germinal centre B-Cell (GCB)-like DLBCL and activated B-Cell (ABC)-like DLBCL. ABC-like DLBCLs are characterised by constitutive NF-kB signalling. Some recent work has highlighted the importance of non-canonical NF-kB pathway is GCB-DLBCL that overexpress BCl6 consistent with their cell of origin. 

Chronic Lymphocytic Leukaemia (CLL):

CLL, which is characterised by clonal expansion of B cells is the most common form of leukaemia in adults. The B cell receptor plays a critical role in driving proliferation of CLL cells. Most CLLs have active Akt/mTOR, ERK and NF-kB signalling pathways as a consequence of the B cell receptor (BCR) being constitutively ON in both an antigen dependent and independent manner. BIRC3 (cIAP2) mutations are often linked with un-favourable prognosis independent of other genetic lesions. Birc3 is an E3 ubiquitin ligase which suppresses non-canonical NF-kB activation. CLLs harbouring BIRC3 mutations have increased NIK levels resulting in constitutively activated non-canonical NF-kB underscored by constitutive p100 processing to p52, resulting in increased expression of the pro-survival molecule Bcl-XL (an NF-kB dependent gene) rendering them less sensitive to conventional chemotherapy.

Mantle Cell lymphoma (MCL):

MCL is a rare B-cell lymphoma that can be aggressive or indolent and often have constitutive activation of BCR signalling. A recent study has reported that MCLs with constitutive canonical NF-κB signalling and low p52 levels (non-canonical) are more sensitive to ibrutinib (BTK inhibitor) treatment than MCLs with genetic abnormalities that result in the activation of the non-canonical NF-κB pathway.

These findings strongly support the hypothesis that the non-canonical NF-κB pathway is associated with lymphomagenesis and resistance to therapy. We therefore postulate that inhibition of the alternative NF-κB pathway may offer a novel targeted therapeutic strategy for diverse B-Cell malignancies and could improve the response to other therapeutic approaches.

 

Collaborators:

Dr Pasquale Fedele
Dr Michael Low
Dr Raffi Gugasyan