Regulation of B Versus T Lymphoid Lineage Fate Decision by the Proto-Oncogene LRF

Abstract

Hematopoietic stem cells in the bone marrow give rise to lymphoid progenitors, which subsequently differentiate into B and T lymphocytes. Here we show that the proto-oncogene LRF plays an essential role in the B versus T lymphoid cell fate decision. We demonstrate that LRF is key for instructing early lymphoid progenitors to develop into B lineage cells by repressing T cell-instructive signals produced by the cell fate signal protein, Notch. We propose a new model for lymphoid lineage commitment, in which LRF acts as a master regulator of B versus T lineage fate decision.All hematopoietic cells are generated from a small subset of pluripotent stem cells (HSCs) via lineage-restricted progenitors. In adult mice, HSCs reside in the bone marrow (BM) and give rise to lymphoid restricted-progenitors (1), which subsequently develop into B and T lymphocytes in the BM and thymus, respectively. This developmental process is coordinated by the differentiation-stage specific expression of distinct sets of genes. Although some of the transcriptional regulators that play key roles in early stages of lymphocyte development are known (2,3), the precise molecular mechanisms by which lymphoid restricted-progenitors are instructed towards B or T cell fates are still largely undefined.

Notch signaling in differentiation and function of dendritic cells

“…HSCs expressing all four members of Notch family (15)(16)(17) are located in bone marrow where they constantly interact with surrounding stromal cells expressing Jagged-1 (13,15,18), Delta-1 (18), and Delta-4 (19). This results in an activation of Notch pathway in HSC.…”

A Novel POK Family Transcription Factor, ZBTB5, Represses Transcription of p21CIP1 Gene

“…BCL-6 (B cell lymphoma transcription factor-6), PLZF, and HIC1 (Hypermethylated In Cancer) have been implicated in nonHodgkin lymphoma, acute promyelocytic leukemia, and spontaneous malignant tumors, respectively (8,9,19). Recently, FBI-1 (also called Pokemon/LRF/ZBTB7A) was characterized as a proto-oncogenic transcription factor regulating ARF and Rb (retinoblastoma) genes (10,20) and also as a critical determinant of B versus T lymphoid lineage fate (21).…”

Role of LRF/Pokemon in lineage fate decisions

“…9,30 Studies regarding the developmental functions of LRF have likewise brought unique insight into the cellular pathways regulated by this protein, especially in the hematopoietic cell lineages (Figure 2). 31,32 Lrf 2/2 embryos exhibit an embryonic lethality around 16.5 days postcoitum as a consequence of extensive anemia. 31 Pandolfi and colleagues defined a strong apoptotic induction of late-stage erythroblasts as the primary cause of lethality in Lrf-null embryos.…”

“…31,32 Lrf 2/2 embryos exhibit an embryonic lethality around 16.5 days postcoitum as a consequence of extensive anemia. 31 Pandolfi and colleagues defined a strong apoptotic induction of late-stage erythroblasts as the primary cause of lethality in Lrf-null embryos. 31 This cell death response occurs despite an intact erythropoietin signaling pathway and in an Arf/p53-independent manner and is associated with strong upregulation of the proapoptotic factor BCL2 interacting mediator of cell death (Bim).…”

“…31 Pandolfi and colleagues defined a strong apoptotic induction of late-stage erythroblasts as the primary cause of lethality in Lrf-null embryos. 31 This cell death response occurs despite an intact erythropoietin signaling pathway and in an Arf/p53-independent manner and is associated with strong upregulation of the proapoptotic factor BCL2 interacting mediator of cell death (Bim). 32 Importantly, these studies identified LRF as a new direct transcriptional target of GATA1 that is essential to the transcriptional repression of the proapoptotic factor Bim, thus defining a novel transcriptional cascade for the suppression of apoptosis during erythroid cell fate decision ( Figure 3).…”