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The roles of ABC transporters in res...

Zong, Yang.

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The roles of ABC transporters in resistance to imatinib and transcriptional regulation of Abcg2 during hematopoiesis.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	The roles of ABC transporters in resistance to imatinib and transcriptional regulation of Abcg2 during hematopoiesis./
作者:	Zong, Yang.
面頁冊數:	136 p.
附註:	Adviser: Brian P. Sorrentino.
Contained By:	Dissertation Abstracts International68-03B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3256247

The roles of ABC transporters in resistance to imatinib and transcriptional regulation of Abcg2 during hematopoiesis.
Zong, Yang.

The roles of ABC transporters in resistance to imatinib and transcriptional regulation of Abcg2 during hematopoiesis. - 136 p.

Adviser: Brian P. Sorrentino.

Thesis (Ph.D.)--The University of Tennessee Health Science Center, 2007.

The development of imatinib has revolutionized the clinical management of chronic myelogenous leukemia (CML). However, increasing evidence indicates that this relatively specific BCR-ABL tyrosine kinase inhibitor predominantly targets mature leukemia cells, but can not eliminate leukemic stem cells. It has been shown that imatinib is the common substrate for ABCG2 and P-glycoprotein (P-gp), two ATP-binding cassette (ABC) transporter proteins that are highly expressed on normal hematopoietic stem cells (HSCs), suggesting that ABC transporters-mediated drug efflux may contribute to imatinib resistance. But the roles of these ABC transporters in stem cell resistance to imatinib, especially their in vivo effects, have not been directly examined. In this study, we took BCR-ABL retroviral transduction and bone marrow transplantation approach, established a CML animal model in which loss of these ABC transporters expression was only restricted in the hematopoietic system. By comparison the in vivo sensitivity to imatinib with wild-type controls, we found that elimination of P-gp or both ABC transporters expression did not improve the hematopoietic responses to imatinib; In the absence of ABCG2 and P-gp, the leukemia initiating cells were not sensitized to imatinib. Moreover, overexpression of either ABC transporters in K562 cells, a BCR-ABL positive human leukemia cell line, only conferred minimal resistance to low levels of imatinib in vitro. Taken together, we conclude that expression of P-gp and ABCG2 do not significantly contribute to imatinib resistance in our CML model systems. In addition, we identified three novel leader exons of mouse Abcg2 gene in this study, which are alternatively used during transcription and yields distinct Abcg2 mRNA isoforms; and the differential expression patterns of Abcg2 transcript isoforms were observed between mouse HSCs and erythroid cells. Furthermore, promoter functional assays using EGFP as a reporter gene demonstrated that the 5' flanking region of HSCs-specific Abcg2 leader exon had promoter activity. In summary, our data show that the expression of Abcg2 during hematopoiesis is transcriptionally regulated by alternative use of multiple leader exons and promoters.Subjects--Topical Terms:

1017686
Biology, Cell.

The roles of ABC transporters in resistance to imatinib and transcriptional regulation of Abcg2 during hematopoiesis.
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520 $a The development of imatinib has revolutionized the clinical management of chronic myelogenous leukemia (CML). However, increasing evidence indicates that this relatively specific BCR-ABL tyrosine kinase inhibitor predominantly targets mature leukemia cells, but can not eliminate leukemic stem cells. It has been shown that imatinib is the common substrate for ABCG2 and P-glycoprotein (P-gp), two ATP-binding cassette (ABC) transporter proteins that are highly expressed on normal hematopoietic stem cells (HSCs), suggesting that ABC transporters-mediated drug efflux may contribute to imatinib resistance. But the roles of these ABC transporters in stem cell resistance to imatinib, especially their in vivo effects, have not been directly examined. In this study, we took BCR-ABL retroviral transduction and bone marrow transplantation approach, established a CML animal model in which loss of these ABC transporters expression was only restricted in the hematopoietic system. By comparison the in vivo sensitivity to imatinib with wild-type controls, we found that elimination of P-gp or both ABC transporters expression did not improve the hematopoietic responses to imatinib; In the absence of ABCG2 and P-gp, the leukemia initiating cells were not sensitized to imatinib. Moreover, overexpression of either ABC transporters in K562 cells, a BCR-ABL positive human leukemia cell line, only conferred minimal resistance to low levels of imatinib in vitro. Taken together, we conclude that expression of P-gp and ABCG2 do not significantly contribute to imatinib resistance in our CML model systems. In addition, we identified three novel leader exons of mouse Abcg2 gene in this study, which are alternatively used during transcription and yields distinct Abcg2 mRNA isoforms; and the differential expression patterns of Abcg2 transcript isoforms were observed between mouse HSCs and erythroid cells. Furthermore, promoter functional assays using EGFP as a reporter gene demonstrated that the 5' flanking region of HSCs-specific Abcg2 leader exon had promoter activity. In summary, our data show that the expression of Abcg2 during hematopoiesis is transcriptionally regulated by alternative use of multiple leader exons and promoters.
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