Biomedical Sciences ETDs

Publication Date

Spring 5-12-2017

Abstract

Through their ability to self-renew and differentiate, hematopoietic stem/progenitor cells (HSPCs) maintain the adult blood and immune systems. The microenvironment, or niche, in which HSPCs reside, serves as a critical regulator of HSPC functions. As previous work has identified the tetraspanin CD82 as a mediator of HSPC-niche interactions, we aimed to determine the mechanism by which this occurs. Our data demonstrate that CD82 expression and scaffolding regulate HSPC interactions with niche components by organizing the α4 integrin subunit into tightly packed nanoclusters. The HSPC niche can also protect acute myeloid leukemia (AML) cells from therapeutics. Therefore, we next examined how CD82 regulates AML cell interactions with the niche. Our data show that the organization of CD82 mediates N-cadherin clustering in a glycosylation-dependent manner for the control of AML-niche interactions. As AML blasts can exhibit uncontrolled signaling, we also examined how CD82 promotes Protein Kinase C α (PKCα) signal transduction in AML. Our data demonstrate that CD82 scaffolding promotes sustained PKCα signaling for the control of AML growth. From these studies, we suspect that targeting the molecular organization of CD82 may provide a means by which AML cells can be released from the bone marrow, while attenuate uncontrolled signaling in AML. Collectively, these data shed light on the mechanisms by which CD82 and the domains within CD82 contribute to cellular adhesion and signaling. We believe that these data offer CD82 and palmitoylation as molecular targets for enhancing HSPC transplantations and improving the efficacy of AML therapeutics.

Keywords

CD82, tetraspanin, integrin, PKCα, hematopoietic, leukemia

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Jennifer Marie Gillette

Second Committee Member

Angela Wandinger-Ness

Third Committee Member

Matthew Campen

Fourth Committee Member

Keith Lidke

Fifth Committee Member

Tione Buranda

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