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Role of AML1 in adult hematopoiesis ...

Sun, Weili.

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Role of AML1 in adult hematopoiesis and alteration of AML1/CBFbeta complex in human leukemia.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Role of AML1 in adult hematopoiesis and alteration of AML1/CBFbeta complex in human leukemia./
作者:	Sun, Weili.
面頁冊數:	164 p.
附註:	Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0670.
Contained By:	Dissertation Abstracts International65-02B.
標題:	Health Sciences, Pathology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3124674
ISBN:	0496719785

Role of AML1 in adult hematopoiesis and alteration of AML1/CBFbeta complex in human leukemia.
Sun, Weili.

Role of AML1 in adult hematopoiesis and alteration of AML1/CBFbeta complex in human leukemia. - 164 p.

Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0670.

Thesis (Ph.D.)--The University of Tennessee Health Science Center, 2004.

The AML1/CBFbeta core-binding factor (CBF) transcription complex is essential for the formation of hematopoietic stem cells (HSC). Moreover, the genes encoding this complex are common targets of genetic alterations in human acute myeloid leukemia (AML). My dissertation has focused on two interrelated questions: (1) What are the functional consequences of AML1 haploinsufficiency on the adult hematopoietic system? (2) What is the range of secondary mutations that can cooperate with alterations in AML1/CBFbeta to induce leukemia?

ISBN: 0496719785Subjects--Topical Terms:

1017854
Health Sciences, Pathology.

Role of AML1 in adult hematopoiesis and alteration of AML1/CBFbeta complex in human leukemia.
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245 1 0 $a Role of AML1 in adult hematopoiesis and alteration of AML1/CBFbeta complex in human leukemia.
300 $a 164 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0670.
500 $a Adviser: James R. Downing.
502 $a Thesis (Ph.D.)--The University of Tennessee Health Science Center, 2004.
520 $a The AML1/CBFbeta core-binding factor (CBF) transcription complex is essential for the formation of hematopoietic stem cells (HSC). Moreover, the genes encoding this complex are common targets of genetic alterations in human acute myeloid leukemia (AML). My dissertation has focused on two interrelated questions: (1) What are the functional consequences of AML1 haploinsufficiency on the adult hematopoietic system? (2) What is the range of secondary mutations that can cooperate with alterations in AML1/CBFbeta to induce leukemia?
520 $a To address the first question, I compared the hematopoietic systems of AML1 +/- and +/+ mice. Loss of a single allele of AML1 resulted in a 50% reduction in the number of long-term repopulating-HSCs. This decrease did not, however, extend to the next level of hematopoietic differentiation. Instead, AML1 +/- mice had an increase in the number of hematopoietic progenitors, an expansion that resulted in enhanced levels of engraftment following transplantation. The expanded pool of AML1 +/- progenitors remained responsive to normal homeostatic mechanisms, and thus the number of mature cells in most lineages remained within normal limits. Two notable exceptions were a decrease in the number of CD4+ T-cells leading to an inversion of the CD4 +:CD8+ T-cell ratio, and a decrease in the number of circulating platelets. Further analysis of megakaryocyte lineage in AML1 +/- mice revealed a partial block in megakaryocyte differentiation. These data demonstrate a dosage-dependent role for AML1/CBFbeta in regulating the "quantity" and "quality" of HSCs and their downstream progenitors, as well as a more restricted role in T-cells and megakaryocytes.
520 $a To address the second question, I analyzed 31 CBF leukemias and 28 non-CBF leukemias for evidence of activating mutations in N-RAS, K-RAS, c-KIT , and FLT3. Remarkably, 48% of the CBF leukemias contained activating mutations in N-RAS or K-RAS , where as only 18% of non-CBF leukemias had these mutations. A direct assessment of the ability of activated N-RAS to cooperate with the expression of AML1-ETO to induce leukemia in mice demonstrated that these two lesions alone were insufficient. These data suggest that in addition to the expression of AML1-ETO and oncogenically activated N-RAS, other genetic lesions are required for full leukemogenesis.
590 $a School code: 0783.
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650 4 $a Health Sciences, Medicine and Surgery. $3 1017756
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710 2 0 $a The University of Tennessee Health Science Center. $3 1262886
773 0 $t Dissertation Abstracts International $g 65-02B.
790 1 0 $a Downing, James R., $e advisor
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791 $a Ph.D.
792 $a 2004
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