Because the tumor suppressor gene KMT2D is also frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer.
Over the past several years, large-scale tumor DNA sequencing studies have revealed the potential involvement of other KMT2 family genes, including heterozygous somatic mutations in the paralogous MLL3/KMT2C and MLL2(4)/KMT2D genes that are now among the most frequently associated with human cancer.
Histone methyltransferase MLL4 is centrally involved in transcriptional regulation and is often mutated in human diseases, including cancer and developmental disorders.
Overall, this work provides insights into the disease mechanism of KMT2D variants and can be extended to other genes, mutations in which also cause developmental syndromes and cancer.
Our data and the Genomics of Drug Sensitivity in Cancer database showed that cancer cells with KMT2D mutations were more sensitive to Aurora kinase inhibitors than were cells without mutations.
Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT.
BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC.
We previously developed a mouse/human chimeric IgG3 Ab (ch128.1) targeting human TfR1, which exhibits direct in vitro cytotoxicity against certain human malignant B cells through TfR1 degradation and iron deprivation. ch128.1 also demonstrates exceptional antitumor activity against the B cell malignancy multiple myeloma (MM) in xenograft models of SCID-Beige mice bearing either disseminated ARH-77 or KMS-11 cells in an early disease setting.
In addition, signaling pathway enrichment analysis indicated that cytokine-cytokine receptor interaction, autophagy, ErbB signaling pathway, microRNAs in cancer and fatty acid metabolism pathways were aberrant in carfilzomib-resistant KMS-11 cells.
An increase in the fission protein Drp1, in the mitophagy protein BNIP3, in the mitochondrial protease CLPP, in the antioxidant and anti-apoptotic protein ALR and in Bcl-2 as well as a decrease in the fusion protein Mfn2 were found in cancer compared to matched non malignant tissue.
Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples.
Overall, we identified here highly recurrent genetic lesions in components of the NF-κB pathway, of NOTCH1 and NOTCH2 as well as KMT2D in OAML and thereby provide major novel insights into the pathogenesis of this B cell malignancy.
The requirement for MLL2 in the maintenance of genome stability in genes helps explain its widespread role in cancer and points to transcription stress as a strong driver in tumorigenesis.
The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach.
We review the most recent evidence on the underlying roles of MLL3/MLL4 and UTX in cancer and highlight key outstanding questions to help drive future research and contribute to our fundamental understanding of cancer and facilitate identification of therapeutic opportunities.
Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort.
We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2(+) cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, lapatinib.
ALR gene expression levels were detected in all cancer tissue samples (N=23), being significantly increased in well/moderately compared to poorly differentiated tumors (p=0.0208).