Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF

Science 316, 860-866 (11 May 2007)

Speaker: 謝家漪                                                    Time: 15:10~16:00, 06/06/ 2007

Commentator: 黎煥耀 老師                                  Place: Room 601

Abstract:

In adult bone marrow (BM), pluripotent hematopoietic stem cells (HSCs) give rise to common lymphoid progenitors (CLP), which subsequently develop into B and T lymphocytes in the BM and thymus, respectively. The B and T lymphopoiesis depends on transcriptional regulators and cytokine at differentiation stages, but the precise molecular mechanisms are still unclear. Previous study indicates that the POK (POZ/BTB and Krüppel)) family proteins play important role in normal hematopoiesis and immune system developments. Proto-oncogene LRF (lymphoma related factor; encoded by Zbtb7a) belongs to the POK family. Zbtb7 inactivation in mouse results in embryonic lethality and impaired cellular differentiation in multiple tissues including the B cell compartment.⁽¹⁾ LRF is broadly expressed in multiple hematopoietic cells. The authors hypothesized that LRF could play a key role in B cell development. First, the authors used Zbtb7a^-/- fetal livers (FLs) and LRF conditional knockout (KO) mice to prove that LRF is essential for both fetal and adult B development. They found that pro-B, pre-B, and immunoglobulin IgM⁺ B cells were drastically reduced, but numbers of prepro-B cells (earliest B cell precursors) were increased and extrathymus double-positive (DP) T cells accumulated in BM via thymus-independent fashion. Furthermore, the authors found that Zbtb7a deletion prepro B cells lost B220 expression and express CD25⁺ and CD44^- on cell surface as normal thymic DN3 (double-positive fraction 3) T cells and aberrantly differentiated to CD4/8 DP T cells. Recent data indicate that Notch commits CLP toward T lineage and constitutive activation of Notch pathway is seen in LRF conditional KO mice.⁽²⁾ LRF conditional KO mice were treated with a Notch signaling inhibitor (GSI), resulting in rescue abnormal B or T cell commitment.⁽²⁾ These data present a new model in which LRF plays a pivotal role as a negative regulator of T lineage commitment by opposing Notch function.

References:

1. Takahiro Maeda. et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278-285 (20 January 2005)

2. Ivan Maillard. et al. Regulation of lymphoid development, differentiation, and function by the  Notch pathway. Annu. Rev. Immunol 23, 945-74. (7 January 2005)