Abstract

Yin Yang 1 (YY1) is a ubiquitously expressed zinc-finger transcriptional regulator that can function as an activator, a repressor, or an initiator binding protein. YY1 has been implicated in the control of cell growth, development, differentiation and tumor suppression. We have recently reported that YY1 regulates the transcription of death receptors in carcinoma and lymphoma and thus, YY1 regulates tumor sensitivity to immune-mediated apoptosis (

Huerta-Yepez, et al.,
2004
,
Oncogene
23
:
4993
–5003
;
Vega, M., et al.,
2005
,
Journal of Immunology
175
:
2174
–2183
). In addition, we have also reported that human prostate tumor tissues overexpress YY1 (Seligson, et al., 2005, International Journal of Oncology 27:131). This study investigated the expression of YY1 in multiple myeloma (MM) with the objective of determining whether YY1 plays a role in the progression and drug- resistance of MM. We have initiated these studies by examining nine bone marrow (BM) samples derived from patients with MM. Immunohistochemical studies were performed for the detection and cytoplasmic or nuclear localization of YY1 in the MM cells and also in adjacent normal mature and immature cells. The intensity of staining by the anti-YY1 antibody was scored and the relative intensity was calculated. Two slides from each patient were analyzed and 200 cells per slide were scored. Mean intensities of all samples were calculated and the data were subjected to statistical analysis. YY1 expression in normal BM was low and primarily of cytoplasmic origin. In contrast, YY1 was significantly overexpressed in MM cells. The mean intensity in the MM was approximately three-four fold higher than that of the normal cells and was primarily of nuclear origin (p-value < 0.05). The signals that control shuttling YY1 are undefined. The expression of YY1 in normal mature and immature cells was low and there was comparable staining in the cytoplasm and the nucleus. Analysis of the cell distribution expressing YY1 by flow cytometry revealed that greater than 50% of the cells in the CD38+ subset expressed YY1. In addition, the MM tumor cells also expressed high level of pleiotrophin (PTN) and the patients had high levels of circulating PTN. PTN is a growth factor for MM and PTN transcription is regulated by an initiator element and could thus be a target of YY1-mediated transcriptional control. These findings suggest that YY1 overexpression may be involved in the pathogenesis of MM and is a potential target for therapeutic intervention. Current studies are aimed at examining the prognostic and diagnostic roles of YY1 and PTN in MM and molecular mechanisms that underlie their overexpression in MM.

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