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Roles of immunoglobulin mu heavy-cha...

Muljo, Stefan Adi.

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Roles of immunoglobulin mu heavy-chain extracellular domain and Abl tyrosine kinase in precursor B lymphocyte development.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Roles of immunoglobulin mu heavy-chain extracellular domain and Abl tyrosine kinase in precursor B lymphocyte development./
作者:	Muljo, Stefan Adi.
面頁冊數:	225 p.
附註:	Adviser: Mark S. Schlissel.
Contained By:	Dissertation Abstracts International63-03B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3046521
ISBN:	0493607110

Roles of immunoglobulin mu heavy-chain extracellular domain and Abl tyrosine kinase in precursor B lymphocyte development.
Muljo, Stefan Adi.

Roles of immunoglobulin mu heavy-chain extracellular domain and Abl tyrosine kinase in precursor B lymphocyte development. - 225 p.

Adviser: Mark S. Schlissel.

Thesis (Ph.D.)--The Johns Hopkins University, 2002.

The development of B lymphocytes in the bone marrow is a highly ordered process with the goal of somatically assembling its antigen receptor through V(D)J recombination. In this process, the immunoglobulin heavy-chain gene gets assembled first, followed by the light-chain gene. Interestingly, a developing B cell monitors its own progress in completing heavy-chain gene rearrangement before it proceeds to the next stage of development to rearrange its light-chain gene. The successful rearrangement of a heavy-chain gene results in the production of an immunoglobulin mu protein that gets deposited on the plasma membrane in a signaling complex called the pre-BCR. The phenomenon known as the pro-to-pre-B cell transition, regulated by this pre-BCR, is reviewed in the introductory chapter. Next, we made and analyzed transgenic mice expressing a mutant pre-BCR missing the variable, CH1, CH2 and CH3 extracellular domains of mu heavy-chain, to determine if these domains play a role in signaling. Our findings suggest that these extracellular portions of the pre-BCR are dispensable for signaling and precursor B (pre-B) cell development. Finally, we consider Abl tyrosine kinase as an antagonist of pre-BCR signaling. Indeed, v-Abl transforms progenitor B (pro-B) cells by virtue of its constitutive kinase activity and results in their developmental arrest. These transformed pro-B cells appear to be prohibited from carrying out precursor B cell developmental events such as rearrangement of immunoglobulin light-chain genes. However, upon treatment with STI571, an inhibitor of Abl kinase, these cells show evidence of bypassing the pro-to-pre-B transition. To determine how v-Abl arrests pre-B cell development and/or how STI571 rescues B cell development, we undertook DNA microarray experiments to compare gene expression in three Abl-transformed lines when untreated or treated with STI571. This strategy led to the identification of numerous transcripts from genes which may be responsible for the transformation effects of v-Abl and the apparent resumption of pre-B cell differentiation upon STI571 treatment. For example, we found that STI571 resulted in the rapid induction of the transcription factors SpiB and IRF4, which may play a role in activating light-chain gene rearrangement both at the kappa and lambda loci. Taken together these findings provide a better understanding of the function of v-Abl in Abelson-transformed pro-B cells. The discovery of genes differentially-regulated by v-Abl provides a foundation for the study of the roles of c-Abl in B cell development <italic>in vivo</italic>. In conclusion, we propose a model in which the tyrosine kinase activity of c-Abl, and perhaps its close relative Arg, is down-regulated in order for B cell development to proceed through the pro-to-pre-B cell transition.

ISBN: 0493607110Subjects--Topical Terms:

1017719
Biology, Molecular.

Roles of immunoglobulin mu heavy-chain extracellular domain and Abl tyrosine kinase in precursor B lymphocyte development.
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520 $a The development of B lymphocytes in the bone marrow is a highly ordered process with the goal of somatically assembling its antigen receptor through V(D)J recombination. In this process, the immunoglobulin heavy-chain gene gets assembled first, followed by the light-chain gene. Interestingly, a developing B cell monitors its own progress in completing heavy-chain gene rearrangement before it proceeds to the next stage of development to rearrange its light-chain gene. The successful rearrangement of a heavy-chain gene results in the production of an immunoglobulin mu protein that gets deposited on the plasma membrane in a signaling complex called the pre-BCR. The phenomenon known as the pro-to-pre-B cell transition, regulated by this pre-BCR, is reviewed in the introductory chapter. Next, we made and analyzed transgenic mice expressing a mutant pre-BCR missing the variable, CH1, CH2 and CH3 extracellular domains of mu heavy-chain, to determine if these domains play a role in signaling. Our findings suggest that these extracellular portions of the pre-BCR are dispensable for signaling and precursor B (pre-B) cell development. Finally, we consider Abl tyrosine kinase as an antagonist of pre-BCR signaling. Indeed, v-Abl transforms progenitor B (pro-B) cells by virtue of its constitutive kinase activity and results in their developmental arrest. These transformed pro-B cells appear to be prohibited from carrying out precursor B cell developmental events such as rearrangement of immunoglobulin light-chain genes. However, upon treatment with STI571, an inhibitor of Abl kinase, these cells show evidence of bypassing the pro-to-pre-B transition. To determine how v-Abl arrests pre-B cell development and/or how STI571 rescues B cell development, we undertook DNA microarray experiments to compare gene expression in three Abl-transformed lines when untreated or treated with STI571. This strategy led to the identification of numerous transcripts from genes which may be responsible for the transformation effects of v-Abl and the apparent resumption of pre-B cell differentiation upon STI571 treatment. For example, we found that STI571 resulted in the rapid induction of the transcription factors SpiB and IRF4, which may play a role in activating light-chain gene rearrangement both at the kappa and lambda loci. Taken together these findings provide a better understanding of the function of v-Abl in Abelson-transformed pro-B cells. The discovery of genes differentially-regulated by v-Abl provides a foundation for the study of the roles of c-Abl in B cell development <italic>in vivo</italic>. In conclusion, we propose a model in which the tyrosine kinase activity of c-Abl, and perhaps its close relative Arg, is down-regulated in order for B cell development to proceed through the pro-to-pre-B cell transition.
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