Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.
OBJECTIVE
Chronic lymphocytic leukaemia (CLL) is a frequent non-Hodgkin lymphoma characterised by a heterogeneous clinical course. Assessment of cell cycle phase kinetics might be important for prediction of clinical behaviour and prognosis.


METHODS
Distribution of neoplastic cells in CLL within the cell cycle was evaluated by determining the labelling indices (LI, i.e. percentage of positive cells) of markers specific for late G1-phase (cyclin E), S-phase (cyclin A), and G2/M-phase (cyclin B1), and Mcm2, a novel marker of proliferative potential, in a large cohort of patients (n = 79) using tissue microarray (TMA) technology. Utilising a combination of these markers, an algorithm was developed--subtracting the combined LIs of cyclin E, cyclin A and cyclin B1 from the LI of Mcm2--to determine the percentage of tumour cells residing in early G1-phase, which is probably a critical state for the malignant potential of CLL.


RESULTS
27.11% of cells had acquired proliferative potential as indicated by expression of Mcm2. Only a small number of cells were found to be in late G1-phase (7.16%), S-phase (3.31%) or G2/M-phase (0.98%), while 15.66% of cells were considered to be in early G1-phase.


CONCLUSIONS
Cell cycle phase distribution can easily be assessed by immunohistochemistry in routinely processed paraffin-embedded specimens. A large number of neoplastic cells in CLL have proliferative potential, with a significant sub-population residing in early G1-phase. Estimates of these cells may identify cases likely to exhibit a more aggressive biological behaviour and adverse clinical course.
Obermann
Ellen C
EC
Institute of Pathology, University of Regensburg, Regensburg, Germany. ellen.obermann@klinik.uni-regensburg.de
Went
Philip
P
Tzankov
Alexandar
A
Pileri
Stefano A
SA
Hofstaedter
Ferdinand
F
Marienhagen
Joerg
J
Stoehr
Robert
R
Dirnhofer
Stephan
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D016213:Cyclins / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D040081:Protein Array Analysis / Q000379:methods
D018797:Cell Cycle Proteins; D016213:Cyclins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2