Genomic p16 abnormalities in the progression of chronic myeloid leukemia into blast crisis: a sequential study in 42 patients.
OBJECTIVE
The molecular abnormalities involved in the progression of chronic myeloid leukemia (CML) are poorly understood. Genetic alterations of the INK4A/ARF locus have been implicated in the lymphoid blast crisis (BC), but sequential studies are not available. The aim of this study was to contribute to a better knowledge of the status of such locus in the different phases of CML and to analyze the prognostic significance of its inactivation.


METHODS
Sequential assessment by quantitative real-time polymerase chain reaction (PCR) and conventional semiquantitative PCR of p16 exon 2 deletions was performed in 42 CML patients in whom paired DNA samples from the chronic phase and the BC were available. Samples of 10 healthy donors and 30 patients with nonleukemic myeloproliferative syndromes served as controls. The methylation status of the promoter region of the p16 gene was also studied by methylation-specific PCR.


RESULTS
The concordance rate between the two PCR techniques was 97.8% (87/89). By real-time PCR, homozygous p16 deletions were found in 6 of 21 patients (29%) with lymphoid BC, whereas they were not observed in chronic-phase CML nor in 21 myeloid BC patients. Hypermethylation of the p16 gene was not detected in any of the lymphoid BC. No specific clinical profile was associated with homozygous p16 deletions. Therapeutic response and survival did not significantly differ in p16-deleted and p16 germline lymphoid BC patients.


CONCLUSIONS
P16 gene deletions are detected in a substantial proportion of lymphoid BC of CML by quantitative real-time PCR analysis, but this is not associated with any clinico-hematological feature other than lymphoid phenotype and does not influence the patients' outcome. Such technique is simple and reliable to assess the p16 gene status.
Hernández-Boluda
Juan-Carlos
JC
Hematology Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.
Cervantes
Francisco
F
Colomer
Dolors
D
Vela
Mari-Carmen
MC
Costa
Dolors
D
Paz
María-Fe
MF
Esteller
Manel
M
Montserrat
Emilio
E
D000328:Adult; D000368:Aged; D001752:Blast Crisis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D019942:Genes, p16; D015894:Genome, Human; D006720:Homozygote; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D016019:Survival Analysis; D016896:Treatment Outcome