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The Impact of Mutations and Downmodulation of LUC7L2 and Other Splicing Factors on Alternative Splicing Landscapes in Leukemic Cells and Malignant Bone Marrow

Hershberger, Courtney E
http://orcid.org/0000-0002-2195-989X
http://rave.ohiolink.edu/etdc/view?acc_num=case1592313710172514

Abstract Details

2020, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Myeloid neoplasms such as myelodysplastic syndromes (MDS), Myelodysplastic/Myeloproliferative (MDS/MPN) syndromes, and acute myeloid leukemias (AML) are characterized by frequent somatic mutations in components of the spliceosome. The mutations occur in both core components of the spliceosome (SF3B1, U2AF1, DDX41, PRPF8) and splicing regulators (SRSF2, ZRSR2), conferring a change of function or resulting in loss of function (LoF). Recently identified somatic frameshift mutation in and deletions encompassing LUC7L2 suggest that loss of function of this putative splicing factor may also contribute to the pathogenesis of myeloid neoplasms through mis-splicing of target genes. LUC7L2 is part of a family that includes LUC7L and LUC7L3. Although the LUC7-like family of proteins are the orthologs of yeast splicing factor Luc7p, little is known about their function in splicing. To understand the impact of LoF of LUC7L2 on alternative splicing (AS) in myeloid neoplasms, we characterized the functions of the LUC7-like family, identifying overlapping and unique roles. We also analyzed the AS patterns of myeloid neoplasm patient samples with down-modulation of LUC7L2 in parallel with patient samples harboring genetic lesions in SF3B1, SRSF2, U2AF1, PRPF8, ZRSR2 and DDX41 to identify commonly mis-spliced targets and dysregulated pathways. The RNA-binding profiling, protein-protein interactions, and alternative splicing analyses in cells and patient samples indicate that LUC7L2 regulates 5’ splice site selection and promotes the exclusion of introns. We functionally characterized these AS events that were regulated by LUC7L2 as well as AS events regulated by the other splicing factors mutated in myeloid neoplasms. Among these 17,300 dysregulated events, hundreds are novel splicing events that are specific to malignant bone marrow, providing targets for diagnostics or therapy. Of the dysregulated AS events that distinguish healthy and diseased bone marrow, intron exclusion was the most enriched type. The excluded introns share features with detained introns, a set of introns that modulate nuclear export. This suggests that the pathogenic role of LUC7L2 and other splicing factors mutated in myeloid neoplasms is the dysregulation of intron detention and loss of translational regulation by an impaired spliceosome.
Richard Padgett, PhD (Advisor)
179 p.
Molecular Biology
pre-mRNA splicing; myeloid neoplasms

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Citations

  • Hershberger, C. E. (2020). The Impact of Mutations and Downmodulation of LUC7L2 and Other Splicing Factors on Alternative Splicing Landscapes in Leukemic Cells and Malignant Bone Marrow [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1592313710172514

    APA Style (7th edition)

  • Hershberger, Courtney. The Impact of Mutations and Downmodulation of LUC7L2 and Other Splicing Factors on Alternative Splicing Landscapes in Leukemic Cells and Malignant Bone Marrow. 2020. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1592313710172514.

    MLA Style (8th edition)

  • Hershberger, Courtney. "The Impact of Mutations and Downmodulation of LUC7L2 and Other Splicing Factors on Alternative Splicing Landscapes in Leukemic Cells and Malignant Bone Marrow." Doctoral dissertation, Case Western Reserve University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1592313710172514

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.