Molecular characterization of an MLL1 fusion and its role in chromosomal instability. Issue 2 (31st December 2018)

• Record Type: Journal Article
• 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.
• Is Part Of: Molecular oncology. Volume 13:Issue 2(2019)
• Page Start: 422
• Page End: 440
• Publication Date: 2018-12-31
• Subjects: chromosomal instability -- chromosomal rearrangement -- fusion proteins -- mitotic checkpoint -- tumor heterogeneity; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12423
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : 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. Abstract : 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.