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


RESULTS
Thirteen 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 to 10% 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.


CONCLUSIONS
Paradoxically, 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.
Dib
Amel
A
Genetics Branch, Center for Cancer Research, National Cancer Institute, Naval Hospital, Bldg 8, Rm 5101, Bethesda, MD20889-5105, USA.
Peterson
Timothy R
TR
Genetics Branch, Center for Cancer Research, National Cancer Institute, Naval Hospital, Bldg 8, Rm 5101, Bethesda, MD20889-5105, USA.|Department of Biology, Masssachusetts Institutes of Technology, Whitehead Institute, 9 Cambridge Center, Rm 359, MA02142, USA.
Raducha-Grace
Laura
L
Genetics Branch, Center for Cancer Research, National Cancer Institute, Naval Hospital, Bldg 8, Rm 5101, Bethesda, MD20889-5105, USA.|University of Pittsburgh School of Medicine, M218 Scaife Hall, Pittsburgh, PA15261, USA.
Zingone
Adriana
A
Genetics Branch, Center for Cancer Research, National Cancer Institute, Naval Hospital, Bldg 8, Rm 5101, Bethesda, MD20889-5105, USA.
Zhan
Fenghuang
F
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 Markham St., #816, Little Rock, AR72205-7199, USA.
Hanamura
Ichiro
I
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 Markham St., #816, Little Rock, AR72205-7199, USA.|Department of Internal Medicine, Division of Hematology, Aichi Medical University, 21 Karimata, Yazako, Nagakute, Aichi-gun, Aichi 480-1195, Japan.
Barlogie
Bart
B
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 Markham St., #816, Little Rock, AR72205-7199, USA.
Shaughnessy
John
J
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 Markham St., #816, Little Rock, AR72205-7199, USA.
Kuehl
W Michael
WM
Genetics Branch, Center for Cancer Research, National Cancer Institute, Naval Hospital, Bldg 8, Rm 5101, Bethesda, MD20889-5105, USA.