​​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).