Although the gene for KMT2D, a histone methyltransferase, is frequently mutated in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL)—the most common types of non-Hodgkin lymphoma—just how this influences tumorigenesis has been obscure. Two simultaneously published studies shed light on this matter: KMT2D, also known as MLL2 or MLL4, is a bona fide tumor suppressor, and its loss of function through genetic changes promotes malignancy.
Most KMT2D mutations are of the truncating, or nonsense, variety, generating a protein that lacks its enzymatic domain. A study from Columbia University in New York, NY, showed that KMT2D can also be inactivated through missense mutations, and that in a small subset of cases, despite an intact gene, the protein is never expressed. KMT2D is responsible for methylating lysine 4 on histone 3 (H3K4), “an epigenetic mark that signals chromatin accessibility and transcriptional activation,” explains senior author Laura Pasqualucci, MD, an associate professor of pathology. “We figured that KMT2D deficiency somehow subverts the epigenetic landscape of B cells to one favoring malignant transformation.”
Pasqualucci and her team created two mouse models that recapitulated different stages of B-cell development: before and after the initiation of germinal centers (GC), sites where B cells proliferate and mature to produce antibodies during a normal immune response. In mice in which the GC reaction had already started, B cells were unaffected by KMT2D deletion and developed normally. However, early removal of KMT2D, before GC initiation, caused mice to display more and larger-sized GCs with higher than usual rates of B-cell proliferation. Transcriptionally, these GCs were also enriched in genes favoring resistance to apoptosis—in all, “a dangerous, potentially tumorigenic environment,” Pasqualucci notes.
In an independent study from Memorial Sloan Kettering Cancer Center (MSKCC) and Weill Cornell Medical College, both in New York, NY, researchers showed that FL incidence rose from 30% to 60% upon KMT2D deletion in mice with a deregulated oncogene, BCL2. (Pasqualucci's team also noted cooperation between deregulated BCL2 and KMT2D loss in increasing lymphoma development, albeit in a different mouse model.) The MSKCC and Weill Cornell researchers then compared gene expression data from human and mouse FL tumors, searching for changes sparked by mutant KMT2D.
“We found that similar genes were downregulated in both humans and mice, including established tumor suppressors like TNFAIP3 and SOCS3,” says Hans-Guido Wendel, MD, a cancer biologist at MSKCC and one of the study's senior authors. Further analyses revealed that these genes are direct targets of KMT2D, with their downregulation driven by mutant-KMT2D–induced loss of H3K4 methylation at enhancer or promoter regions, or both.
“We think we're off to a good start in answering the question ‘What are KMT2D's targets, and what does its loss of function do?'” Wendel says. He and Pasqualucci consider their studies parallel investigations that document KMT2D's previously unknown tumor-suppressor role in lymphoid malignancies. Pasqualucci also notes that KMT2D lesions are likely among the earliest acquired by B cells en route to malignant transformation.
Although Wendel's group observed that in DLBCL treated with standard chemotherapy, KMT2D mutations did not affect outcomes like overall or progression-free survival, whether this mutation status could influence the efficacy of newer targeted therapies remains an open question, he says. Meanwhile, inhibiting enzymes like JARID1 and LSD1, which normally demethylate H3K4, may present another therapeutic option for KMT2D-deficient lymphomas.
“The idea is that this could rebalance the methylation landscape,” Wendel explains, “and it's one we're exploring more closely.”
- ©2015 American Association for Cancer Research.
Volume 5, Issue 12
