Date of Graduation

5-2015

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Hesham M. Amin, M.D.

Committee Member

Russell Broaddus, M.D., Ph.D.

Committee Member

Jeffrey Frost, Ph.D.

Committee Member

Gary E. Gallick, Ph.D.

Committee Member

Joseph A. Ludwig, M.D.

Abstract

The anaplastic lymphoma kinase (ALK) is a single chain transmembrane receptor tyrosine kinase that belongs to the insulin receptor superfamily. Other members of this superfamily include the insulin receptor (IR), type I insulin-like growth factor receptor (IGF-IR), and the leukocyte tyrosine kinase. The common structural finding among these tyrosine kinases is the YXXXYY motif present within their respective tyrosine kinase domains. Binding of its ligands causes ALK receptor homodimerization and protein kinase activation. ALK has been previously shown to play a significant role during early developmental stages. In human embryos, the expression of ALK is mainly seen in the nervous system but it decreases at birth. A variety of structural rearrangements have been identified in the ALK gene, such as mutations, overexpression, and translocations, often leading to the production of oncogenic proteins found in several different types of human cancers, such as nucleophosmin-anaplastic lymphoma kinase-expressing anaplastic large-cell lymphoma (NPM-ALK+ ALCL). The oncogenic potential of NPM-ALK has been demonstrated by several studies using in vitro assays as well as transgenic mouse models.

NPM-ALK+ ALCL is an aggressive subset of T-cell lymphoma that predominantly occurs in children and young adults. It comprises approximately 85% of ALK+ ALCL cases and is characterized by the translocation t(2;5)(p23;q35) that leads to the fusion between the NPM gene on chromosome 5q35 and the ALK gene on chromosome 2p23 generating the NPM-ALK oncogene, which encodes the expression of NPM-ALK chimeric tyrosine kinase. NPM-ALK induces lymphomagenic effects through the formation of the constitutively activated NPM-ALK/NPM-ALK homodimers, which phosphorylate/activate downstream survival-promoting proteins including JAK/STAT, PI3K/AKT, and MAP kinase. NPM-ALK resides in the cytoplasm; nonetheless, it is also capable of forming the wild type NPM/NPM-ALK heterodimers that translocate to the nucleus through the nuclear localization signal site present in wild type NPM.

IGF-IR is a homodimeric protein that is composed of two extracellular α and two transmembranous β subunits connected by disulfide bonds. Similar to ALK, its expression plays an important role during early developmental stages. Mouse models have confirmed the importance of IGF-IR in prenatal and postnatal growth through its interactions with the growth hormone. The result of activation of IGF-IR during these stages is survival and proliferation of cells resulting in developmental growth of tissues such as skeletal and cardiac muscles. It also plays a critical role during growth of the mammary gland during pregnancy and lactation. It has been previously shown that Igf1r null mice develop generalized organ hypoplasia, such as developmental delays in bone ossification, abnormalities in the central nervous system, and they prematurely die because of underdevelopment of their lungs that leads to respiratory failure. Recently, it has been shown that IGF-IR overexpression significantly contributes to the establishment and progression of different types of cancer and to the emergence of therapeutic resistance. These effects have been extensively investigated in solid tumors including breast, prostate, lung, ovary, skin, and soft tissue cancers.

We have recently demonstrated that, compared with normal human T lymphocytes and reactive lymphoid tissues, the expression and activation of IGF-IR are remarkably upregulated in NPM-ALK+ ALCL. We also demonstrated that IGF-IR physically associates and directly interacts with NPM-ALK. Nonetheless, the exact mechanisms for the up-regulation of IGF-IR and NPM-ALK in this lymphoma are not fully characterized. We hypothesized that multilevel deregulation of survival mechanisms contributes to aberrant NPM-ALK and IGF-IR expression, which supports the survival and progression of NPM-ALK+ ALCL.

Keywords

IGF-IR, NPM-ALK, lymphoma, cancer signaling, miRNA, SUMOylation, gene regulation, cancer