Divergent expression of cyclin-dependent kinase inhibitors (CKI) and p14ARF/p16 beta in non-Hodgkin's lymphomas and chronic lymphocytic leukemia.
Chronic B-cell lymphocytic leukaemia (CLL) and low-grade B-cell Non Hodgkin's lymphomas (Lg-NHL) are characterized by slow accumulation of neoplastic cells arrested in the G0/G1 phase of the cell cycle. In contrast, proliferation rates are high in aggressive B-cell lymphomas (Hg-NHL). Divergent expression of cyclin-dependent kinase inhibitors (CKI) in the cell cycle may contribute to these differences. We analysed CLL as well as low and high grade B-cell NHL for expression of G1-specific and universal CKI by competitive RT-PCR and immunostaining. p16(INK4A) expression was low in all types of neoplasms. Highest p14(ARF) /p16 beta expression levels were found in normal lymphocytes. Expression of this CKI was significantly lower in CLL, but still higher in CLL than in the lymphomas (median 27 vs. 3 mRNA transcripts x 10(3), p = 0.0001). p14(ARF) /p16 beta immunostaining correlated with mRNA expression. Highest p21 mRNA levels were found in CLL, but three of four CLL with abundant p21 mRNA production were negative on immunostaining. High grade lymphomas showed markedly decreased p21 expression (3.9 in Hg-NHL vs. 12 in Lg-NHL and 29 in CLL; values expressed as mRNA transcripts x 10(3), p < 0.009). mRNA and protein expression of p27 was considerably higher in CLL than in the lymphomas. Differential CKI expression in various B-cell neoplasias may provide important biological markers, if not the molecular underpinning of their different cell cycle kinetics. Targeted interference with such genes governing cell cycle control in lymphoid neoplasia may pave the way towards new treatment strategies.
Pabst
T
T
Department of Clinical Pathology, Institute of Medical Oncology, University of Berne, Switzerland.
Peters
U R
UR
Tinguely
M
M
Schwaller
J
J
Tschan
M
M
Aebi
S
S
Vonlanthen
S
S
Borisch
B
B
Betticher
D C
DC
Zimmermann
A
A
Tobler
A
A
Fey
M F
MF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002455:Cell Division; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27