Transcriptional Regulation of B-Cell Development
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P231-232
2025-12-17
27
The generation of lymphoid cells from HSCs is dependent on expression of the Ets family member PU.1. Mice in which Spi1, the gene encoding PU.1, is not expressed produce erythroid and megakaryocytic but not monocytic, granulocytic, and lymphoid cells and die during the fetal or neonatal period. PU.1 regulates several events that promote B lineage specification, including expression of CD135 (Flt3), which is expressed on immature progenitors such as the CLP, CD45R(B220), and CD127 (IL-7Rα). However, deletion of Spi1 at the CLP stage of development has no negative effect on B-cell development, indicating that PU.1 expression is not required once B-cell specification has initiated.
Further B lineage specification is dependent on expression of additional transcription factors including early B-cell factor (EBF) and the E2A-encoded splice variants E12 and E47. Each of these DNA binding proteins regulates the expression of a variety of B-lineage target genes. For example, Ebf1 regulates the expression of Igα, VpreB, λ5, and Pax5 and represses genes associated with alternative lineage fates. Mice in which EBF and E2A are not expressed exhibit an almost complete block in B-cell development at the pro-B-cell stage.
Ebf1 and E2A-expressing progenitors can still exhibit some non-B lineage potential, indicating that the expression of these DNA binding proteins does not result in absolute B lineage commitment. Instead, this is dependent on expression of the Pax5 transcription fac tor.6 Phenotypically identifiable B-cell precursors are present in Pax5 knock-out mice, and these cells can differentiate into myeloid, T, and natural killer (NK) cells. However, if the gene encoding Pax5 is introduced into Pax5-deficient precursors, this developmental promiscuity ceases. Thus, a critical function of Pax5 is to suppress non-B lineage potential. For example, Pax5 may repress expression of myeloid growth factor receptors and inhibit T-cell potential by antagonizing expression of Notch1, a cell-surface receptor required for commitment to the T-cell lineage. Continued Pax5 expression is necessary to maintain lineage fidelity even in relatively mature B cells.
Additional transcription factors, such as Ikaros, Satb1, Foxo1, IRF4, IRF8, c-Myb, Gfi1, Miz-1, Bcl6, and Bach2, function at various times during B-cell development. For example, IRF4 is involved with Ig recombination and the attenuation of IL-7 signaling, thus promoting the transition from the pre-B to B cell stages of maturation. IRF8, along with PU.1, regulates EBF expression. Ikaros plays a role in regulating expression of key B lineage genes such as IL-7Rα and EBF and promoting B lineage commitment. c-Myb has been shown to synergize with PU.1 to activate IL-7 receptor (IL 7R) gene transcription. Focused reviews should be consulted for a full discussion of these and additional transcriptional regulators of B lymphopoiesis.
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