Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival.
We have investigated the significance of telomerase activity (TA) and telomere length (TL) in multiple myeloma (MM). The analyses were undertaken on CD138+ MM cells isolated from the marrow of 183 patients either at diagnosis or in relapse. There was heterogeneity in telomerase expression; 36% of the patients had TA levels comparable to those detected in normal plasma cells, and 13% of patients had levels 1- to 4-fold greater than in a neuroblastoma cell line control. The TL of MM cells was significantly shorter than that of the patients' own leukocytes; in 25% of patients, the TL measured less than 4.0 kbp. Analysis of TL distribution indicated selective TA-mediated stabilization of shorter telomeres when mean TL fell below 5.5 kbp. Unusually long (10.8-15.0 kbp) telomeres were observed in 7 patients, and low TA was observed in 5 of 7 patients, suggesting the operation of a TA-independent pathway of telomere stabilization. A strong negative correlation existed between TA and TL or platelet count. TL negatively correlated with age and with interleukin-6 (IL-6) and beta2-microglobulin levels. Various cytogenetic abnormalities, including those associated with poor prognosis, strongly correlated with TA and, to a lesser extent, with short TL. High TA and short TL defined a subgroup of patients with poor prognosis. At 1 year the survival rate in patients with TA levels lower than 25% of neuroblastoma control and TL greater than 5.5 kbp was 82%, whereas in patients with higher TA and shorter TL the survival rate was 63% (P =.004). The 2-year survival rate for patients with TA levels lower than 25% was 81%, and it was 52% in those with higher TA levels (P <.0001).
Wu
Kai-Da
KD
Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Orme
Lisa M
LM
Shaughnessy
John
J
Jacobson
Joth
J
Barlogie
Bart
B
Moore
Malcolm A S
MA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D002869:Chromosome Aberrations; D002882:Chromosomes, Human, Pair 13; D020732:Cytogenetic Analysis; D005260:Female; D006098:Granulocytes / Q000648:ultrastructure; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008214:Lymphocytes / Q000648:ultrastructure; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000648:ultrastructure; D010950:Plasma Cells / Q000276:immunology / Q000648:ultrastructure; D011379:Prognosis; D011509:Proteoglycans / Q000032:analysis; D015996:Survival Rate; D053668:Syndecan-1; D053667:Syndecans; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000648:ultrastructure*; D001613:beta 2-Microglobulin / Q000097:blood
D015850:Interleukin-6; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508241:SDC1 protein, human; D053668:Syndecan-1; D053667:Syndecans; D001613:beta 2-Microglobulin; D019098:Telomerase