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Our previous studies indicate that reduction of lipocalin 2 (mouse 24p3) expression by either anti-sense or siRNA approaches strongly reduces the overgrowth of BCR-ABL+ mouse myeloid 32D in marrow and spleen of NOD/SCID mice. In this study, we used the mouse bone marrow transplant model to further explore the role of 24p3 in BCR-ABL-induced leukemia. Consistent with our previous findings, when using non-irradiated mice as recipient, donor marrow cells expressing BCR-ABL but lacking 24p3 did not cause leukemia or any disease after 75 days, whereas all mice receiving wild type BCR-ABL donor cells died with CML-like disease. An agar clone of the BCR-ABL+ human CML cell line K562 (C5) that secretes relatively high levels of lipocalin 2 (human NGAL) induced suppression of hematopoiesis in spleen and marrow of mice, leading to early death in contrast to parental K562 or K562 clone (C6) expressing low amounts of NGAL. Compared with K562 cells, overexpressing NGAL in K562 led to a higher apoptosis rate and an atrophy phenotype in the spleen of the inoculated mice. Plasma from both leukemic mice and CML patients showed elevated lipocalin 2 levels compared with healthy individuals. Moreover, we found that a primary stable cell line from wild-type mouse marrow cells expressing BCR-ABL caused solid tumors in nude mice whereas a similar BCR-ABL+ cell line from 24p3 null mice did not. These findings demonstrate that lipocalin 2 has at least two functions related to tumorigenesis, one involving apoptosis induction of normal hematopoietic cells and the other being tissue invasion by leukemia cells.Oncogene (2008) 27, 6110–6119; doi:10.1038/onc.2008.209; published online 28 July 2008 [ABSTRACT FROM AUTHOR]

Erythroid differentiation-associated gene (EDAG) is considered to be a human hematopoiesis-specific gene. Here, we reported that downregulation of EDAG protein in K562 cells resulted in inhibition of growth and colony formation, and enhancement of sensitivity to erythroid differentiation induced by hemin. Overexpression of EDAG in HL-60 cells significantly blocked the expression of the monocyte/macrophage differentiation marker CD11b after pentahydroxytiglia myristate acetate induction. Moreover, overexpression of EDAG in pro-B Ba/F3 cells prolonged survival and increased the expression of c-Myc, Bcl-2 and Bcl-xL in the absence of interleukin-3 (IL-3). Furthermore, we showed that EDAG enhanced the transcriptional activity of nuclear factor-kappa B (NF-?B), and high DNA-binding activity of NF-?B was sustained in Ba/F3 EDAG cells after IL-3 was withdrawn. Inhibition of NF-?B activity resulted in promoting Ba/F3 EDAG cells death. These results suggest that EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of NF-?B.Cell Death and Differentiation (2004) 11, 1299-1308. doi:10.1038/sj.cdd.4401490 Published online 27 August 2004 [ABSTRACT FROM AUTHOR]