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100 1 a| Whelan, Jarrett Thomas.?| UNAUTHORIZED;

245 10 a| Enforced expression of HoxA9 in B-lineage ALL promotes survival and proliferation of leukemic cells /c| by Jarrett Thomas Whelan.;

260 a| [Greenville, N.C.] :b| East Carolina University,c| 2009.;

300 a| 153 pages :b| illustrations (some color), digital, PDF file.;

336 a| text2| rdacontent;

337 a| computer2| rdamedia;

338 a| online resource2| rdacarrier;

490 1 a| ECU Brody School of Medicine thesis;

500 a| Presented to the faculty of the Department of Microbiology and Immunology.;

500 a| Advisor: Fred E. Bertrand.;

500 a| Title from PDF t.p. (viewed September 27, 2010).;

502 b| Ph.D.c| East Carolina Universityd| 2009.;

504 a| Includes bibliographical references.;

520 3 a| HoxA9 is frequently overexpressed in acute myeloid leukemia, myelodysplastic syndrome and a subset of acute lymphoblastic leukemia. In mouse models, HoxA9 has been shown to promote leukemogenesis. In spite of a seemingly central role in initiating leukemia, and in acting as a cofactor to promote leukemic cell growth and survival, the mechanistic pathways altered by HoxA9 overexpression, which promote the growth and survival of leukemia, are not well defined. We have developed a stromal cell dependent model of human B-lineage ALL with conditional HoxA9 activity. The HoxA9-negative pre-B cell ALL cell line, BLIN-2, was stably transduced with a retrovirus bearing HoxA9 fused to the hormone binding domain of the human estrogen receptor. HoxA9 activity is stimulated by the addition of 4-hydroxytamoxifen to the growth medium. BLIN-2 cells have an absolute dependency on stromal cell contact for growth and survival, which permits the testing of the HoxA9 mediated effects in the context of the tumor microenvironment. Induction of HoxA9 activity in BLIN-2 resulted in increased proliferation in the absence of stromal cell support and induction of surface expression of IGF-1R. Through the use of specific IGF-1R inhibitors, we demonstrated that the proliferative response upon HoxA9 stimulation was the result of signaling through the induced IGF-1R. In addition to promoting stromal cell independent proliferation, enforced induction of HoxA9 activity promoted apoptotic resistance to stromal cell/growth factor withdrawal. Inhibition of IGF-1R signaling did not abrogate the anti-apoptotic effects of HoxA9, but did result in decreased proliferation. Models of IGF-1R typically attribute anti-apoptotic effects of IGF-1R signaling to Akt signaling, whereas the proliferative effects are mediated via the ERK pathway. No changes in Akt phosphorylation were observed in BLIN-2 cells with activated HoxA9, but levels of phospho-ERK were increased. These results are consistent with a role for HoxA9 induction of IGF-1R promoting proliferation, but not apoptotic resistance. Overall, these data indicate that enforced expression of HoxA9 in leukemia promotes proliferation via an IGF-1R dependent pathway and that HoxA9 promotes apoptotic resistance to stromal cell/growth factor withdrawal through a pathway that is independent of IGF-1R signaling.;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

650 0 a| Leukemia.=| ^A4603;

650 2 a| Leukemia, Myeloidx| prevention & control.=| ^A1023137;

650 2 a| Neoplasm Proteins.=| ^A1023153;

653 a| Health Sciences, Immunology;

653 a| Health Sciences, Oncology;

700 1 a| Bertrand, Fred E.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Microbiology and Immunology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine thesis.=| ^A964744;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/1903;

949 a| Click on web addressw| ASISh| JOYNER101;

949 a| Click on web addressw| ASISh| HSL111;

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998 a| 2151526;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 2151526-1001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 12/11/2009x| ETDz| HERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 2151526-2001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 12/11/2009x| ETDz| JERESOURCE;

Enforced expression of HoxA9 in B-lineage ALL promotes survival and proliferation of leukemic cells / by Jarrett Thomas Whelan.

Author/creator	Whelan, Jarrett Thomas
Other author	Bertrand, Fred E.
Other author	East Carolina University. Department of Microbiology and Immunology.
Format	Theses and dissertations
Publication Info	[Greenville, N.C.] : East Carolina University, 2009.
Description	153 pages : illustrations (some color), digital, PDF file.
Supplemental Content	Access via ScholarShip
Subjects	Leukemia. Leukemia, Myeloid--prevention & control. Neoplasm Proteins.

Series	ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744
Summary	HoxA9 is frequently overexpressed in acute myeloid leukemia, myelodysplastic syndrome and a subset of acute lymphoblastic leukemia. In mouse models, HoxA9 has been shown to promote leukemogenesis. In spite of a seemingly central role in initiating leukemia, and in acting as a cofactor to promote leukemic cell growth and survival, the mechanistic pathways altered by HoxA9 overexpression, which promote the growth and survival of leukemia, are not well defined. We have developed a stromal cell dependent model of human B-lineage ALL with conditional HoxA9 activity. The HoxA9-negative pre-B cell ALL cell line, BLIN-2, was stably transduced with a retrovirus bearing HoxA9 fused to the hormone binding domain of the human estrogen receptor. HoxA9 activity is stimulated by the addition of 4-hydroxytamoxifen to the growth medium. BLIN-2 cells have an absolute dependency on stromal cell contact for growth and survival, which permits the testing of the HoxA9 mediated effects in the context of the tumor microenvironment. Induction of HoxA9 activity in BLIN-2 resulted in increased proliferation in the absence of stromal cell support and induction of surface expression of IGF-1R. Through the use of specific IGF-1R inhibitors, we demonstrated that the proliferative response upon HoxA9 stimulation was the result of signaling through the induced IGF-1R. In addition to promoting stromal cell independent proliferation, enforced induction of HoxA9 activity promoted apoptotic resistance to stromal cell/growth factor withdrawal. Inhibition of IGF-1R signaling did not abrogate the anti-apoptotic effects of HoxA9, but did result in decreased proliferation. Models of IGF-1R typically attribute anti-apoptotic effects of IGF-1R signaling to Akt signaling, whereas the proliferative effects are mediated via the ERK pathway. No changes in Akt phosphorylation were observed in BLIN-2 cells with activated HoxA9, but levels of phospho-ERK were increased. These results are consistent with a role for HoxA9 induction of IGF-1R promoting proliferation, but not apoptotic resistance. Overall, these data indicate that enforced expression of HoxA9 in leukemia promotes proliferation via an IGF-1R dependent pathway and that HoxA9 promotes apoptotic resistance to stromal cell/growth factor withdrawal through a pathway that is independent of IGF-1R signaling.
General note	Presented to the faculty of the Department of Microbiology and Immunology.
General note	Advisor: Fred E. Bertrand.
General note	Title from PDF t.p. (viewed September 27, 2010).
Dissertation note	Ph.D. East Carolina University 2009.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Enforced expression of HoxA9 in B-lineage ALL promotes survival and proliferation of leukemic cells / by Jarrett Thomas Whelan.

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