Molecular characterization of an MLL1 fusion and its role in chromosomal instability

Chromosomal rearrangements involving the mixed‐lineage leukemia (MLL1) gene are common in a unique group of acute leukemias, with more than 100 fusion partners in this malignancy alone. However, do these fusions occur or have a role in solid tumors? We performed extensive network analyses of MLL1‐fu...

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Bibliographic Details
Published in:	Molecular oncology Vol. 13; no. 2; pp. 422 - 440
Main Authors:	Parameswaran, Sreejit, Vizeacoumar, Frederick S., Kalyanasundaram Bhanumathy, Kalpana, Qin, Fujun, Islam, Md. Fahmid, Toosi, Behzad M., Cunningham, Chelsea E., Mousseau, Darrell D., Uppalapati, Maruti C., Stirling, Peter C., Wu, Yuliang, Bonham, Keith, Freywald, Andrew, Li, Hui, Vizeacoumar, Franco J.
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-02-2019 John Wiley and Sons Inc Wiley
Subjects:	Androgen receptors Base Sequence Biomarkers, Tumor - metabolism Cancer Carcinogenesis - metabolism Carcinogenesis - pathology CD44 antigen Cell Cycle Proteins - genetics chromosomal instability Chromosomal Instability - genetics chromosomal rearrangement Chromosome rearrangements Chromosomes Clone Cells Cloning Deoxyribonucleic acid DNA Ethylenediaminetetraacetic acid Flow cytometry fusion proteins Gene expression Gene Regulatory Networks Genetic aspects Genomes Genomic instability HCT116 Cells Humans Lethality Leukemia Malignancy mitotic checkpoint Models, Biological Myeloid-Lymphoid Leukemia Protein - genetics Myeloid-Lymphoid Leukemia Protein - metabolism Oncogene Fusion Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Phenotype Prostate Prostate cancer Proteins Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Scientific equipment and supplies industry Signal transduction Solid tumors Stem cells tumor heterogeneity Tumors Vectors (Biology) Canada United States United States > US Saskatchewan Canada fusion proteins mitotic checkpoint chromosomal rearrangement chromosomal instability tumor heterogeneity
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Summary:	Chromosomal rearrangements involving the mixed‐lineage leukemia (MLL1) gene are common in a unique group of acute leukemias, with more than 100 fusion partners in this malignancy alone. However, do these fusions occur or have a role in solid tumors? We performed extensive network analyses of MLL1‐fusion partners in patient datasets, revealing that multiple MLL1‐fusion partners exhibited significant interactions with the androgen‐receptor signaling pathway. Further exploration of tumor sequence data from TCGA predicts the presence of MLL1 fusions with truncated SET domain in prostate tumors. To investigate the physiological relevance of MLL1 fusions in solid tumors, we engineered a truncated version of MLL1 by fusing it with one of its known fusion partners, ZC3H13, to use as a model system. Functional characterization with cell‐based assays revealed that MLL1‐ZC3H13 fusion induced chromosomal instability, affected mitotic progression, and enhanced tumorsphere formation. The MLL1‐ZC3H13 chimera consistently increased the expression of a cancer stem cell marker (CD44); in addition, we detected potential collateral lethality between DOT1L and MLL1 fusions. Our work reveals that MLL1 fusions are likely prevalent in solid tumors and exhibit a potential pro‐tumorigenic role. This work reveals that mixed‐lineage leukemia (MLL1) fusions are likely prevalent in solid tumors and exhibit a potential pro‐tumorigenic role. Systematic analyses of the tumor‐sequencing data have identified potential MLL‐fusions in prostate tumors. Functional characterization of one such recombination using cell‐based assays revealed that this MLL1‐fusion induced chromosomal instability, affected mitotic progression, and enhanced tumorsphere formation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1574-7891 1878-0261
DOI:	10.1002/1878-0261.12423