Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression.

Amel Dib,Ichiro Hanamura,W Michael Kuehl,Bart Barlogie,Timothy R Peterson,John Shaughnessy,Fenghuang Zhan,Laura Raducha-Grace,Adriana Zingone

doi:10.1186/1747-1028-1-23

Abstract

BackgroundA high proliferative capacity of tumor cells usually is associated with shortened patient survival. Disruption of the RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, is a frequent target of oncogenic events that are thought to contribute to increased proliferation during tumor progression. Previously, we determined that p18INK4c, an essential gene for normal plasma cell differentiation, was bi-allelically deleted in five of sixteen multiple myeloma (MM) cell lines. The present study was undertaken to investigate a possible role of p18INK4c in increased proliferation of myeloma tumors as they progress.ResultsThirteen of 40 (33%) human myeloma cell lines do not express normal p18INK4c, with bi-allelic deletion of p18 in twelve, and expression of a mutated p18 fragment in one. Bi-allelic deletion of p18, which appears to be a late progression event, has a prevalence of about 2% in 261 multiple myeloma (MM) tumors, but the prevalence is 6 to10% in the 50 tumors with a high expression-based proliferation index. Paradoxically, 24 of 40 (60%) MM cell lines, and 30 of 50 (60%) MM tumors with a high proliferation index express an increased level of p18 RNA compared to normal bone marrow plasma cells, whereas this occurs in only five of the 151 (3%) MM tumors with a low proliferation index. Tumor progression is often accompanied by increased p18 expression and an increased proliferation index. Retroviral-mediated expression of exogenous p18 results in marked growth inhibition in three MM cell lines that express little or no endogenous p18, but has no effect in another MM cell line that already expresses a high level of p18.ConclusionParadoxically, although loss of p18 appears to contribute to increased proliferation of nearly 10% of MM tumors, most MM cell lines and proliferative MM tumors have increased expression of p18. Apart from a small fraction of cell lines and tumors that have inactivated the RB1 protein, it is not yet clear how other MM cell lines and tumors have become insensitive to the anti-proliferative effects of increased p18 expression.

Highlights

A high proliferative capacity of tumor cells usually is associated with shortened patient survival
Western blots detect an apparently normal p18 protein at a level that parallels the level of p18 RNA in 27 of these human myeloma cell lines (HMCL), but no p18 protein was detected in KMS-12BM
The consensus minimum deletion region in 13 HMCL selectively targets the p18INK4c gene The p18INK4c gene is located on chromosome band 1p32.3, 9 kb centromeric to the Fas associated factor 1 (FAF1) gene, which encodes a receptor (TNFRSF6) that is able to mediate apoptosis initiated by interaction with external FAS ligand (TNFSF6) [11]

Summary

Introduction

A high proliferative capacity of tumor cells usually is associated with shortened patient survival. Disruption of the RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, is a frequent target of oncogenic events that are thought to contribute to increased proliferation during tumor progression. The RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, has a central role in the regulation of proliferation, senescence, and differentiation in most tissues [1,2]. Cell cycle arrest is tightly coupled to terminal differentiation of B cells into plasma cells, a process that is temporally correlated with an increased expression of p18INK4c [3,4]. Mice that are null for p18 developed widespread organomegaly, with an increased incidence of pituitary tumors [5]. P18 null B cells did not differentiate into normal plasma cells [7]

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