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Tsanov, Kaloyan M

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Tsanov

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Kaloyan M

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Tsanov, Kaloyan M
Author's Publications: search.filters.isAuthorOfPublication.4257f28e-85c5-4073-ab6c-2fb8b3161f97

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    Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma
    (2016) Powers, John T.; Tsanov, Kaloyan M; Pearson, Daniel; Roels, Frederik; Spina, Catherine S; Ebright, Richard; Seligson, Marc; de Soysa, Yvanka; Cahan, Patrick; Theiβen, Jessica; Tu, Ho-Chou; Han, A Reum; Kurek, Kyle C; LaPier, Grace S; Osborne, Jihan; Ross, Samantha J; Cesana, Marcella; Collins, James; Berthold, Frank; Daley, George
    Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis.
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    An Embryonic Stem Cell-Based System for Rapid Analysis of Transcriptional Enhancers
    (Wiley Periodicals, Inc., 2012) Tsanov, Kaloyan M; Nishi, Yuichi; Peterson, Kevin A; Liu, Jing; Baetscher, Manfred; McMahon, Andrew P.
    With the growing use of genome-wide screens for cis-regulatory elements, there is a pressing need for platforms that enable fast and cost-effective experimental validation of identified hits in relevant developmental and tissue contexts. Here, we describe a murine embryonic stem cell (ESC)-based system that facilitates rapid analysis of putative transcriptional enhancers. Candidate enhancers are targeted with high efficiency to a defined genomic locus via recombinase-mediated cassette exchange. Targeted ESCs are subsequently differentiated in vitro into desired cell types, where enhancer activity is monitored by reporter gene expression. As a proof of principle, we analyzed a previously characterized, Sonic hedgehog (Shh)-dependent, V3 interneuron progenitor (pV3)-specific enhancer for the Nkx2.2 gene, and observed highly specific enhancer activity. Given the broad potential of ESCs to generate a spectrum of cell types, this system can serve as an effective platform for the characterization of gene regulatory networks controlling cell fate specification and cell function.