Research Highlights

Cyclin D1 and DNA damage response in mantle cell lymphoma
Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that is characterized by cyclin D1 overexpression. Elevated cyclin D1 levels were strongly associated with aggressive clinical manifestations. The Ngo laboratory uncovered a role for cyclin D1 in preserving genomic stability during DNA replication (Mohanty et al., Leuk Lymphoma 2017). They also discovered that cyclin D1 inhibition induced activity of molecules that promote tumor survival. To circumvent this tumor protective response, Ngo’s group performed a synthetic lethal RNA interference (RNAi) screen and uncovered multiple targets that play essential roles in the DNA damage response pathway. These results confirmed their hypothesis that targeting DNA damage response factors could provide a rational combination with anti-cyclin D1 as an effective strategy for treating mantle cell lymphoma.
 
Overcoming therapy resistance in mantle cell lymphoma
The emergence of ibrutinib therapy, which targets the Bruton’s tyrosine kinase (BTK), has revolutionized the treatment of MCL. However, a third of patients are not responding to this therapy, necessitating a better understanding of ibrutinib resistance and development of more effective treatment approaches. The Ngo laboratory found that somatic mutations in cyclin D1 produced a more stable protein and promoted ibrutinib resistance in MCL cells (Mohanty et al., Oncotarget 2016). These results led to a hypothesis that deregulated turnover of cyclin D1 and potentially other oncoproteins may contribute to therapy resistance of cancer cells. The Ngo’s group are actively testing this hypothesis in many lymphoid tumors.
 
Novel mechanisms of lymphomagenesis
The neural transcription factor SOX11 is aberrantly expressed in MCL, but its functional significance and mechanisms of deregulated expression are not known. The Ngo’s group has identified that cyclin D1 plays a key role in regulating SOX11 expression through its ability to alter HDAC1 function. Overexpression of cyclin D1 results in HDAC1 eviction from local chromatin and accumulation of active histone marks (H3K9/14Ac) at the SOX11 locus, leading to increased SOX11 transcription. The laboratory’s current goal is to unravel the complexity of SOX11 transcriptional regulation and to identify potential targets that disrupt oncogenic cooperation between cyclin D1 and SOX11.