Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2008. / Title from first page of PDF file (viewed Aug. 1, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 120-127).

Indiana University-Purdue University Indianapolis (IUPUI) / Acute Myeloid Leukemia (AML) is the most common hematologic malignancy. Malglycemia is a disorder of glucose metabolism and includes hyperglycemia, hypoglycemia and the combination of hyperglycemia and hypoglycemia. Malglycemia has been shown to occur frequently during hospitalization among critical care patients and has been associated with increased risk of sepsis and mortality. Little is known, however, about the prevalence and role of malglycemia on the health outcomes of AML patients hospitalized for initial induction therapy. Malglycemia may be of particular importance to the patient with AML because, researchers have found that malglycemia may promote cellular changes which facilitate the progression of cancer, alter treatment response, and attenuate immune response. The purpose of this study was to determine the prevalence of malglycemia (hyperglycemia, hypoglycemia or the combination) and to examine its role on a comprehensive set of health outcomes (neutropenic days, infection, and septicemia, and sepsis, induction hospital length of stay, complete remission and mortality) in AML patients hospitalized for initial induction therapy. A retrospective cohort study design was used. Records of 103 AML patients, hospitalized for initial induction chemotherapy were reviewed. Results of the study showed that 98% of the AML patients had at least one episode of hyperglycemia, with a prevalence rate of 33% over the entire induction inpatient hospitalization for this population. All patients noted with hyperglycemia also had hypoglycemia and thus, the prevalence rate of hypoglycemia alone could not be determined. Prevalence of the combination of hyperglycemia and hypoglycemia was 1.4 %. Although not statistically significant, a trend was noted for AML patients with hyperglycemia to experience more days with neutropenia, greater numbers of infection, sepsis, septicemia and death (mortality) than patients without hyperglycemia during induction treatment. Patients with the combination of hyperglycemia and hypoglycemia also experienced an increased risk of developing septicemia (p = .025) and sepsis (p =.057). Future studies with larger sample sizes are needed to confirm these findings.

Indiana University-Purdue University Indianapolis (IUPUI) / Gain-of-function mutations in the KIT receptor tyrosine kinase have been associated with highly malignant human neoplasms. In particular, an acquired somatic mutation at codon 816 in the second catalytic domain of KIT involving an aspartic acid to valine substitution is found in patients with systemic mastocytosis (SM) and acute myeloid leukemia (AML). The presence of this mutation in SM and AML is associated with poor prognosis and overall survival. This mutation changes the conformation of the KIT receptor resulting in altered substrate recognition and constitutive tyrosine autophosphorylation leading to constitutive ligand independent growth. As there are currently no efficacious therapeutic agents against this mutation, this study sought to define novel therapeutic targets that contribute to aberrant signaling downstream from KITD816V that promote transformation of primary hematopoietic stem/progenitor cells in diseases such as AML and SM. This study shows that oncogenic KITD814V (murine homolog) induced myeloproliferative neoplasms (MPN) occurs in the absence of ligand stimulation, and that intracellular tyrosines are important for KITD814V-induced MPN. Among the seven intracellular tyrosines examined, tyrosine 719 alone has a unique role in regulating KITD814V-induced proliferation and survival. Residue tyrosine 719 is vital for activation of the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85α, downstream from KITD814V. Downstream effectors of the PI3K signaling pathway, in of leukemic cells bearing KITD814V with an allosteric inhibitor of Pak or its genetic inactivation results in growth repression due to enhanced apoptosis. To assess the role of Rac GEFs in KITD814V induced transformation, EHop-016, an inhibitor of Rac, was used to specifically target Vav1, and found to be a potent inhibitor of human and murine leukemic cell growth. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of MPN and rescued the associated pathology in mice. These studies provide insight on mechanisms and potential novel therapeutic targets for hematological malignancies harboring an oncogenic KIT mutation.