Date of Award

2011

Degree Name

Doctor of Philosophy

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Vincent E Sollars

Second Advisor

Richard Niles

Third Advisor

Todd Green

Abstract

Hematopoiesis is maintained by a proper balance between self renewal and multipotent differentiation of the hematopoietic stem cells (HSC). Acute myelogenous leukemia (AML) is characterized by the blockage in the differentiation of HSC, while self renewal and proliferation is preserved. It is important to understand the mechanisms involved in the inhibition of hematopoietic differentiation and maintenance of the HSC state in order to develop better therapies for AML. In these studies I have explored the role of Hsp90, omega-3 fatty acids and YB-1 in hematopoietic differentiation. EML, a hematopoietic precursor cell line, was used as a model for the hematopoietic system in these studies. My preliminary data showed the activation of Wnt signaling upon inhibition of Hsp90 in EML cells. This data suggested the involvement of Hsp90 in the regulation of Wnt signaling in EML cells. Moreover, my initial data with fatty acid studies indicated that omega-3 fatty acids could affect Wnt signaling in EML cells. Unfortunately, further progression of both these studies was marred by variability in my data. In my latest study, I have identified YB-1 as a marker involved in the maintenance of the hematopoietic stem cell state. YB-1 was found to be highly expressed in the EML cell line and in the mouse bone marrow-derived HSC and myeloid progenitor cells. In addition, YB-1 expression was downregulated during myeloid differentiation in retinoic acid (RA) and granulocyte macrophage colony stimulating factor (GM-CSF) treated EML cells, as well as in the granulocytes derived from mouse bone marrow. Further, abnormal YB-1 expression was observed in myeloid leukemic cell lines. Knockdown of YB-1 expression and arsenic trioxide treatment (As2O3) in erythroleukemic, K562 cell line resulted in apoptosis and inhibition of cell proliferation. Most importantly, these treatments led to the induction of megakaryocytic differentiation in these cells. Overall my data suggests that increased expression of YB-1 in the leukemic cells contributes to the leukemic cell properties by promoting cell proliferation, cell survival and blocking cell differentiation. Thus, YB-1 could be a potential target for therapy in myeloid leukemia.

Subject(s)

Hematopoiesis.

Lymphatics - Cancer.

Acute myeloid leukemia.

Stem cells - Research.

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