Regulation of the Cyclin A1 Protein Is Associated with Its Differential Subcellular Localization in Hematopoietic and Leukemic Cells

Regulation of the cyclin A1 protein is associated with its differential subcellular localization in hematopoietic and leukemic cells

Jenny Ekberg1,Go¨ ran Landberg1, Caroline Holm1, Johan Richter2, Debra J Wolgemuth3,4 and Jenny Liao Persson*,1

1Division of Pathology, Department of Laboratory Medicine, Lund University, University Hospital, Malmo¨ S-205 02 Sweden; 2Division of Molecular Medicine and Gene Therapy, BMC, Lund S-221 84 Sweden; 3Department of Genetics and Development, The Center for Reproductive Sciences and The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA; 4Department of Obstetrics and Gynecology, The Center for Reproductive Sciences and The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA

An important role of the cell cycle regulatory protein cells. For example, all-trans retinoic acid (ATRA) can cyclin A1 in the development of acute myeloid leukemia induce clinical remission in patients with acute promye- (AML) was previously demonstrated in a transgenic locytic leukemia (APL), a subtype of acute myeloid mouse model. We have now turned our attention to study leukemia (AML) (He et al., 1999; Zhu et al., 1999). speciﬁc aspects of the activity and subcellular distribution Certain leukemic cell lines respond to ATRA by of cyclin A1 using bone marrow samples from normal switching from a state of uncontrolled proliferation, donors and patients with AML, as well as leukemic cell typical for malignant cells, to a state in which the cells lines. We show that the localization of cyclin A1 in normal undergo terminal differentiation like normal hemato- hematopoietic cells is nuclear, whereas in leukemic cells poietic cells (Dimberg et al., 2002). It has been suggested from AML patients and cell lines, it is predominantly that the role of ATRA in promoting myeloid differ- cytoplasmic. In leukemic cell lines treated with all-trans entiation in APL might be related to its ability to restore retinoic acid (ATRA), cyclin A1 localized to the nucleus. a normal subcellular localization of several leukemia- Further, there was a direct interaction between cyclin A1 associated proteins such as PML and other nuclear and cyclin-dependent kinase 1, as well as a major ATRA domain-associated proteins (Koken et al., 1994; Weis receptor, RARa, in ATRA-treated cells but not in et al., 1994, Faretta et al., 2001). RARa, a nuclear untreated leukemic cells. Our results indicate that the hormone receptor, mediates the response to ATRA by altered intracellular distribution of cyclin A1 in leukemic releasing corepressors and recruiting coactivators and cells correlates with the status of the leukemic phenotype. leads to the induction of target genes for granulocytic Oncogene (2004) 23, 9082–9089. doi:10.1038/sj.onc.1208090 differentiation (He et al., 1999). Published online 18 October 2004 Cell cycle control plays a fundamental role in cell differentiation and growth. The proper regulation of Keywords: cyclin A1; AML; subcellular localization; the cell cycle machinery, including cyclins, cyclin-depen- CDK1; RARa dent kinases (CDK), and the negative regulators CDK inhibitors (CDKI), is critical for hematopoiesis (Furukawa, 1997, 1998; Dao and Nolta, 1999). Several reports have also emphasized the importance of the Introduction dynamic subcellular localization of cell cycle regulatory molecules such as the CDKIs p27 and p21 for the Hematopoietic stem cells undergo a decision either to differentiation of hematopoietic cells (Yaroslavskiy self-renew and remain pluripotent o