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Etchin, Julia

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Etchin

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Julia

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Etchin, Julia

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2013 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.850d1201-7698-4145-a0e4-7998e95d6f03

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    Small genomic insertions form enhancers that misregulate oncogenes
    (Nature Publishing Group, 2017) Abraham, Brian J.; Hnisz, Denes; Weintraub, Abraham S.; Kwiatkowski, Nicholas; Li, Charles H.; Li, Zhaodong; Weichert-Leahey, Nina; Rahman, Sunniyat; Liu, Yu; Etchin, Julia; Li, Benshang; Shen, Shuhong; Lee, Tong Ihn; Zhang, Jinghui; Look, A.; Mansour, Marc R.; Young, Richard A.
    The non-coding regions of tumour cell genomes harbour a considerable fraction of total DNA sequence variation, but the functional contribution of these variants to tumorigenesis is ill-defined. Among these non-coding variants, somatic insertions are among the least well characterized due to challenges with interpreting short-read DNA sequences. Here, using a combination of Chip-seq to enrich enhancer DNA and a computational approach with multiple DNA alignment procedures, we identify enhancer-associated small insertion variants. Among the 102 tumour cell genomes we analyse, small insertions are frequently observed in enhancer DNA sequences near known oncogenes. Further study of one insertion, somatically acquired in primary leukaemia tumour genomes, reveals that it nucleates formation of an active enhancer that drives expression of the LMO2 oncogene. The approach described here to identify enhancer-associated small insertion variants provides a foundation for further study of these abnormalities across human cancers.
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    Antileukemic Activity of Nuclear Export Inhibitors that Spare Normal Hematopoietic Cells
    (Nature Publishing Group, 2013) Etchin, Julia; Sun, Q; Kentsis, Alex; Farmer, A; Zhang, Z C; Sanda, Takaomi; Mansour, M R; Barcelo, C; McCauley, D; Kauffman, M; Shacham, S; Christie, A L; Kung, A L; Rodig, Scott; Chook, Y M; Look, A.
    Drugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable potencies and a broad range of cytotoxic effects. Here, we report the structural analysis and antileukemic activity of a new generation of small-molecule inhibitors of CRM1. Designated selective inhibitors of nuclear export (SINE), these compounds were developed using molecular modeling to screen a small virtual library of compounds against the nuclear export signal (NES) groove of CRM1. The 2.2-Å crystal structure of the CRM1-Ran-RanBP1 complex bound to KPT-251, a representative molecule of this class of inhibitors, shows that the drug occupies part of the groove in CRM1 that is usually occupied by the NES, but penetrates much deeper into the groove and blocks CRM1-directed protein export. SINE inhibitors exhibit potent antileukemic activity, inducing apoptosis at nanomolar concentrations in a panel of 14 human acute myeloid leukemia (AML) cell lines representing different molecular subtypes of the disease. When administered orally to immunodeficient mice engrafted with human AML cells, KPT-251 had potent antileukemic activity with negligible toxicity to normal hematopoietic cells. Thus, KPT-SINE CRM1 antagonists represent a novel class of drugs that warrant further testing in AML patients.