Unmasking the Role of the Ubiquitin Ligase FBXW7 Beta Isoform in B-Lymphopoiesis and Leukemia / Scarlett Y Yang.

Format:

Book

Thesis/Dissertation

Author/Creator:

Yang, Scarlett Y., author.

Contributor:

University of Pennsylvania. Immunology, degree granting institution.

Language:

English

Subjects (All):

Immunology.

Oncology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Local Subjects:

Immunology.

Oncology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Physical Description:

1 online resource (94 pages)

Contained In:

Dissertations Abstracts International 84-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Ann Arbor : ProQuest Dissertations & Theses, 2022

Language Note:

English

Summary:

Non-canonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow and tonsil donors, performed RNA-seq, and examined transcript variants. We identified 150 genes that harbor local splicing variations in all pairwise comparisons. One of them encodes FBXW7, an E3 ubiquitin ligase implicated as a cancer driver in several blood cancers. Surprisingly, we discovered that in normal human pro-B cells, the predominant transcript utilized an alternative first exon to produce the poorly characterized FBXW7β isoform, previously thought to be restricted to neural tissues. The FBXW7β transcript was also abundant in cell lines and primary samples of pediatric B-cell acute lymphoblastic leukemia (B-ALL), which originates in the bone marrow. When overexpressed in a heterologous cell system, this transcript yielded the expected protein product, as judged by anti-FLAG immunoblotting and mass spectrometry. Furthermore, in REH B-ALL cells, FBXW7β mRNA was the only FBXW7 isoform enriched in the polyribosome fraction. To shed light on possible functions of FBXW7β, we utilized gain- and loss-of-function approaches and identified an FBXW7β-dependent inflammatory gene signature, apparent in a subset of B-ALL with high FBXW7β expression. This signature contained several members of the TNF superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7β expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis and responses to anti-cancer therapies.

Notes:

Source: Dissertations Abstracts International, Volume: 84-08, Section: B.

Advisors: Thomas-Tikhonenko, Andrei; Committee members: Tong, Wei; Lynch, Kristen W.; Allman, David M.; Barash, Yoseph; Elenitoba-Johnson, Kojo S. J.

Department: Immunology.

Ph.D. University of Pennsylvania 2022.

Local Notes:

School code: 0175

ISBN:

9798374412598

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.