1. ¹Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
2. ²Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
3. ³Department of Veterinary Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
4. ⁴Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
5. ⁵Institution of Systems Biology, Seattle, WA, USA
6. ⁶Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and Exploratory Research for Advanced Technology (ERAYO), Japan Science and Technology Corporation, Osaka, Japan
7. ⁷Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Correspondence: Professor R Arlinghaus, Department of Molecular Pathology, The University of Texas, MD Anderson Cancer Center, 7435 Fannin Street, Unit 951, Houston, TX 77030, USA. E-mail: rarlingh@mdanderson.org

Received 4 April 2008; Revised 21 May 2008; Accepted 3 June 2008; Published online 28 July 2008.

Abstract

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.