LRF (leukemia/lymphoma related factor), which is encoded by the ZBTB7A gene, was originally identified as a PLZF (promyelocytic leukemia zinc finger) homologue interacting with BCL6 (B-cell lymphoma 6). LRF is a transcription factor that belongs to the BTB-zinc finger protein family and broadly expressed in hematopoietic lineage cells. Its expression is particularly high in erythroblasts and germinal center B-cells.
LRF is a potent repressor of fetal globin expression.
Hemoglobinopathies, such as sickle cell disease (SCD) and thalassemia, are caused by mutations in adult-type globins and are among the greatest public health concerns worldwide. One promising approach is to reactivate repressed expression of fetal-type hemoglobin (HbF) in adult erythroid cells. We recently found that LRF is a potent repressor of fetal globin expression in adult erythroid cells (Masuda et al. Science 2016).
LRF is necessary for terminal erythroid differentiation.
Conventional LRF knockout (KO) mice are embryonic lethal at around 16.5 d.p.c. due to anemia. LRF-deficient fetal liver erythroblasts exhibit maturation defects at later stages of erythroid differentiation (Maeda et al. Div Cell 2009). LRF conditional KO mice (LRF flox/flox Mx1-Cre) exhibit a mild macrocytic anemia due to inefficient erythroid terminal differentiation (Maeda et al. Div Cell 2009).
LRF functions as a proto-oncoprotein in B cells.
LRF functions as a porto-oncogene: when over-expressed, it causes lymphoma in mice. LRF protein is highly expressed in Non-Hodgkin Lymphoma tissues (Maeda et al. Nature 2005).
LRF is necessary for germinal center (GC) B cell proliferation and survival in mice. B-cell specific LRF knockout mice exhibit impaired GCB cell proliferation (Sakurai et al. JCI 2011).
LRF is required for lymphoid fate determination.
LRF regulates lymphoid fate determination and HSC maintenance by repressing Notch ligand DLL4 in erythroblasts. Dll4, a Notch ligand, is “de-repressed” in LRF-deficient erythroblasts. When HSCs expressing Notch1 are stimulated by Dll4, they receive T-instructive signals and differentiate into T cells in the BM, resulting in HSC depletion (Maeda et al. Science 2007; Lee et al. Blood 2013).