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Differential contributions of c-KIT ...

Jean Nick, Heidi.

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Differential contributions of c-KIT activating mutations to promotion of AML1-ETO associated neoplasia.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Differential contributions of c-KIT activating mutations to promotion of AML1-ETO associated neoplasia./
作者:	Jean Nick, Heidi.
面頁冊數:	109 p.
附註:	Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: .
Contained By:	Dissertation Abstracts International72-08B.
標題:	Health Sciences, Pathology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3457141
ISBN:	9781124671772

Differential contributions of c-KIT activating mutations to promotion of AML1-ETO associated neoplasia.
Jean Nick, Heidi.

Differential contributions of c-KIT activating mutations to promotion of AML1-ETO associated neoplasia. - 109 p.

Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: .

Thesis (Ph.D.)--The University of Alabama at Birmingham, 2011.

The t(8;21) translocation, which generates an AML1-ETO fusion protein (also known as RUNX1-ETO), is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). Murine studies have demonstrated that AML1-ETO promotes the accumulation of myeloid progenitor cells with self-renewal capability and impaired differentiation capacity. However, AML1-ETO+ mice do not progress to AML in the absence of additional mutations, suggesting that expression of the translocation is insufficient for leukemogenesis. This hypothesis is supported by studies demonstrating the persistence of AML1-ETO-expressing hematopoietic progenitors obtained from patients in long-term clinical remission.

ISBN: 9781124671772Subjects--Topical Terms:

1017854
Health Sciences, Pathology.

Differential contributions of c-KIT activating mutations to promotion of AML1-ETO associated neoplasia.
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245 1 0 $a Differential contributions of c-KIT activating mutations to promotion of AML1-ETO associated neoplasia.
300 $a 109 p.
500 $a Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: .
500 $a Adviser: Christopher A. Klug.
502 $a Thesis (Ph.D.)--The University of Alabama at Birmingham, 2011.
520 $a The t(8;21) translocation, which generates an AML1-ETO fusion protein (also known as RUNX1-ETO), is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). Murine studies have demonstrated that AML1-ETO promotes the accumulation of myeloid progenitor cells with self-renewal capability and impaired differentiation capacity. However, AML1-ETO+ mice do not progress to AML in the absence of additional mutations, suggesting that expression of the translocation is insufficient for leukemogenesis. This hypothesis is supported by studies demonstrating the persistence of AML1-ETO-expressing hematopoietic progenitors obtained from patients in long-term clinical remission.
520 $a Mutations affecting receptor tyrosine kinases, particularly c-KIT, are commonly detected in t(8;21)+ AML. In AML1-ETO+ patient samples, differing classes of activating c-KIT mutations have been observed with varying prevalence. The most common (12-48%) involves mutations that occur in the activation loop of the phosphotransferase domain, like D814V, while another involves deletions within exon 8, a region mediating receptor dimerization (2-13% of cases). To formally investigate whether distinct activating c-Kit mutations differ in their capacity to drive AML1-ETO-associated AML, we used a retroviral transduction strategy to co-express AML1-ETO with c-Kit D814V or a representative exon 8 mutant (c-KitT417IDelta418-419 ) in murine bone marrow progenitor cells used to reconstitute lethally irradiated mice. Analysis of reconstituted mice showed that AML1-ETO;c-Kit D814V co-expression resulted in three non-overlapping phenotypes. In 45% of animals, an AML of relatively short latency and frequent granulocytic sarcoma was noted. Other mice exhibited a rapidly fatal myeloproliferative neoplasm (35%) or a lethal, short-latency pre-B-cell leukemia (20%). In contrast, AML1-ETO;c-KitT417IDelta418-419 co-expression promoted exclusively AML in a fraction (51%) of reconstituted mice with a median latency nearly double that observed in AML1-ETO;c-KitD814V mice that developed AML. Analysis of clonality indicated that acquisition of oncogenic events in addition to AML1-ETO and an activated c-Kit receptor were necessary for transformation in all cases. The neoplastic phenotype differences between AML1-ETO;c-Kit D814V and AML1-ETO;c-KitT417IDelta418-419 mice indicate that distinct activating c-Kit mutants differ in leukemogenic potential, which could account for the disparity in prevalence of each c-KIT mutation concurrent with AML1-ETO in human AML.
520 $a Keywords: acute myeloid leukemia, AML1-ETO, c-Kit, hematopoiesis
590 $a School code: 0005.
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650 4 $a Health Sciences, Oncology. $3 1018566
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710 2 $a The University of Alabama at Birmingham. $b Microbiology. $3 1684956
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790 1 0 $a Klug, Christopher A., $e advisor
790 1 0 $a Justement, Louis B. $e committee member
790 1 0 $a Kabarowski, Janusz H. $e committee member
790 1 0 $a Lopez, Richard D. $e committee member
790 1 0 $a Ryan, Thomas M. $e committee member
790 $a 0005
791 $a Ph.D.
792 $a 2011
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