A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia.
BACKGROUND
MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL.


METHODS
We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgV(H) ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities.


RESULTS
A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgV(H) from those with mutated IgV(H) . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germ-line or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (P<0.001).


CONCLUSIONS
A unique microRNA signature is associated with prognostic factors and disease progression in CLL. Mutations in microRNA transcripts are common and may have functional importance.
Calin
George Adrian
GA
Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
Ferracin
Manuela
M
Cimmino
Amelia
A
Di Leva
Gianpiero
G
Shimizu
Masayoshi
M
Wojcik
Sylwia E
SE
Iorio
Marilena V
MV
Visone
Rosa
R
Sever
Nurettin Ilfer
NI
Fabbri
Muller
M
Iuliano
Rodolfo
R
Palumbo
Tiziana
T
Pichiorri
Flavia
F
Roldo
Claudia
C
Garzon
Ramiro
R
Sevignani
Cinzia
C
Rassenti
Laura
L
Alder
Hansjuerg
H
Volinia
Stefano
S
Liu
Chang-gong
CG
Kipps
Thomas J
TJ
Negrini
Massimo
M
Croce
Carlo M
CM
D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D051746:ZAP-70 Protein-Tyrosine Kinase
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D035683:MicroRNAs; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human