PU.1 is a tumor suppressor for B cell malignancies

PU.1 is a critical transcription factor for differentiation of both myeloid and lymphoid cells. PU.1 knockout mice are embryonic lethal or die soon after birth, and those mice do not have granulocytes, monocytes/ macrophages, or B cells [1, 2]. PU.1 is expressed in granulocytes, monocytes/macrophages, and B cells, but not in erythrocytes, megakaryocytes, or T cells. It was recently shown that PU.1 is an essential transcription factor for T H 9 cell differentiation using a conditional mouse knockout model [3]. Collectively, these data show that PU.1 is essential for the differentiation of most hematopoietic lineages. In contrast, PU.1 expression in conditional knockout mice of a 14 kb upstream enhancer element (URE) of PU.1 gene reduced to 20% of wild type, and those mice developed acute myeloid leukemia (AML) and B-CLL-like disease [4]. These data show that PU.1 expression is tightly regulated in specific lineage cells and the decreased PU.1 expression results in various hematological malignancies. Meanwhile, PU.1 function is not well understood in B cells. In the early lymphoid commitment stage, the loss of PU.1 expression leads to complete failure of lymphoid differentiation in both B and T cells. In late B cell development, the loss of PU.1 expression induced by a CD19-Cre system had no effect on B cell differentiation [5], suggesting that PU.1 may not be necessary for mature B cell differentiation. However, this does not explain the facts that in conventional PU.1 knockout mice B cells are defective, but T cells are not, and that decreased PU.1 expression (noted above) induced B-CLL-like disease. These observations prompted us to try to elucidate the function of PU.1 in B cell malignancies, starting with multiple myeloma, a malignancy of plasma cells. Most myeloma cell lines have lost PU.1 expression, while primary myeloma cells from patients have decreased PU.1 expression and normal plasma cells have relatively high levels. We have demonstrated that downregulation of PU.1 in myeloma cell lines is caused by an epigenetic mechanism. In addition, conditional expression of PU.1 using a Tet-off system induced growth arrest and apoptosis in myeloma cell lines [6]. This suggests that PU.1 may be a tumor suppressor for multiple myeloma. In another B cell lymphoid malignancy, classical Hodgkin lymphoma, PU.1 is also downregulated through promoter methylation. Therefore, we speculated that PU.1 might also be a tumor suppressor for classical Hodgkin lymphoma. Thus, we introduced conditional PU.1 expression in the classical Hodgkin lymphoma cell lines, …