17-E2A updated review

17-E2A updated review - The roles of transcription factors...

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Unformatted text preview: The roles of transcription factors in B lymphocyte commitment, development, and transformation Emma Smith and Mikael Sigvardsson 1 Department for Hematopoietic Stemcellbiology, Stemcell Center, Lund University, Sweden Abstract: Studies of normal blood cell develop- ment and malignant transformation of hematopoi- etic cells have shown that the correctly regulated expression of stage- and lineage-specific genes is a key issue in hematopoiesis. Experiments in trans- genic mice have defined a number of transcription factors such as SCL/Tal, core-binding factor/acute myeloid leukemia, and c-myb, all crucial for the establishment of definitive hematopoiesis and devel- opment of all blood cell lineages. Other regulators such as IKAROS, E47/E2A, early B cell factor, Sox-4, and B cell-specific activator protein (Pax-5) appear crucial, more or less selectively, for B lym- phopoiesis, allowing for detailed analysis of the development of this lineage. In addition, several of these transcription factors are found translocated in human tumors, often resulting in aberrant gene expression or production of modified proteins. This article concerns the role of transcription fac- tors in B lymphoid development with special focus on lineage initiation and commitment events but also to some extent on the roles of transcription factors in human B lymphoid malignancies. J. Leu- koc. Biol. 75: 973–981; 2004. Key Words: hematopoietic cells z early B cell factor z B cell- specific activator protein z E2A z B lineage malignancies HALLMARKS OF B LYMPHOCYTE DEVELOPMENT The pluripotent hematopoietic stem cell (HSC) gives rise to all mature cell types in the blood (lymphoid, myeloid, and ery- throid) by differentiating through intermediate stage progenitor cells displaying a progressive restriction in multilineage po- tential [1]. The understanding of the processes regulating the differentiation of a HSC into a mature immunoglobulin (Ig)- secreting plasma cell has increased during recent years, mak- ing it possible to use this pathway as a model system for cell development. B cell development in mouse and humans has been extensively reviewed [1–3] ( Fig. 1 ), and the following section will just briefly mention defined stages of B cell devel- opment and functional roles of some of the proteins produced at specific times in development. An apparently common feature between man and mouse is the need for the pre-B cell receptor, composed of the newly rearranged Ig heavy chain and surrogate light chains, to allow the early pre-B cells to enter the late pre-B cell stage [4]. The ordered rearrangement process, proceeding from D–J of both alleles to V–D–J rearrangements [3–5], produces a large num- ber of antigen-binding specificities. However, several of these newly formed genes will encode truncated proteins as a result of junctional diversity introducing frame-shift mutations or stop codons. To avoid production of immunoincompetent B cells, there exists a need to investigate whether the recombination...
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17-E2A updated review - The roles of transcription factors...

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