We have studied the MMSET (also known as WHSC1 or NSD2) protein a histone lysine methyltransferase identified by its rearrangement with the immunoglobulin locus aberrant overexpression in multiple myeloma (MM). Overexpression of MMSET leads to dramatic shifts in chromatin modification and gene expression and stimulates cell growth. MMSET overexpression has also been linked to aberrant cell growth and invasive properties in prostate, lung cancer and neuroblastoma. More recently we and others described a recurrent point mutation (E1099K) in the SET domain of MMSET in acute lymphoblastic leukemia (ALL). The importance of this mutation is growing as genome sequencing showed that this mutation in present in ~10% of cases of mantle cell lymphoma (MCL) and is found in ~10-20% of cases of relapsed pediatric ALL. Collectively these data indicate that MMSET and the pathways it regulates represent therapeutic targets in MM and other malignancies. Our overarching hypothesis is that overexpression or gain of function mutations of MMSET alter gene regulation leading to the pathogenesis of MM and to the progression of ALL. While some target genes may be activated in common across these tumors, our preliminary data suggests that MMSET mutation dysregulates a unique set of genes in ALL. By constructing genetically engineered cell line and mouse models of models of the action of the E1099K mutation we will ascertain the detailed molecular mechanisms, by which MMSETE1099K affects gene expression, identify critical target genes and pathways and uncover new therapeutic opportunities for cancer treatment.
Our specific aims will be:
Aim 1 : Evaluate the Biological Activity of a Recurrent Point Mutation of MMSET in Malignancy. We will determine the mechanism of action of this protein and how it alters histone methylation levels. Using newly prepared CRISPR/CAS9 edited cell lines we will determine how mutant MMSET modulates cell growth and response to therapy.
Aim 2 : Define the Genetic Targets and Pathways Affected by Oncogenic Mutations of MMSET. Preliminary data suggest that mutant MMSET activates a different set of genes in ALL compared to those affected in MM. Using genetically edited cell lines, we will determine how the mutation alters chromatin configuration across the genome and identify critical genes and pathways of its oncogenic action.
Aim 3 : Evaluate the Ability of Mutant MMSET to Collaborate with Known MM and ALL Oncogenes. We will cross a newly created knockin mouse expressing MMSETE1099K with established mouse models of ALL and MM to determine how this disease allele may drive pathogenesis and progression of disease.
In this project we will study how the MMSET, a histone lysine methyl transferase, overexpressed in multiple myeloma and mutated in other lymphoid malignancies can lead to tumor development. We will use cell models to elucidate the mechanisms by which MMSET alters chromatin and stimulates malignant cell growth and create animal models of disease associated with MMSET mutation.
| Swaroop, Alok; Oyer, Jon A; Will, Christine M et al. (2018) An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene : |
| Bennett, Richard L; Licht, Jonathan D (2018) Targeting Epigenetics in Cancer. Annu Rev Pharmacol Toxicol 58:187-207 |
| Bennett, Richard L; Swaroop, Alok; Troche, Catalina et al. (2017) The Role of Nuclear Receptor-Binding SET Domain Family Histone Lysine Methyltransferases in Cancer. Cold Spring Harb Perspect Med 7: |
| Dupéré-Richer, Daphné; Licht, Jonathan D (2017) Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma. Curr Opin Hematol 24:336-344 |
| Shah, M Y; Martinez-Garcia, E; Phillip, J M et al. (2016) MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents. Oncogene 35:5905-5915 |
