The prognostic significance of p16INK4a/p14ARF and p15INK4b deletions in adult acute lymphoblastic leukemia.
Cytogenetic/molecular abnormalities significantly influence the prognosis of patients with acute leukemia. Recently, two genes, p16INK4a and p15INK4b, encoding two cyclin-dependent kinase inhibitor proteins of the INK4 family of Mr 15,000 and 16,000, respectively, have been localized to 9p21. Remarkably, the p16INK4a locus has been found to encode a second protein, p14ARF, known as p19ARF in mice, with a distinct reading frame. Like p16INK4a, p14ARF is involved in cell cycle regulation, blocking cells at the G1 restriction point through the activity of MDM-2 and p53. We studied bone marrow samples of 42 newly diagnosed and untreated patients with acute lymphoblastic leukemia for the incidence of deletions of p16INK4a/p14ARF and p15INK4b using Southern blot analysis and determined the clinical outcome with regard to complete remission (CR) duration, event-free survival, and overall survival. We found deletions of p16INK4a/p14ARF in 17 of 42 patients (40%), with homozygous deletions in 11 of 42 patients (26%) and hemizygous deletions in 6 of 42 patients (14%). The gene for p15INK4b was codeleted in most, but not all, cases and was never deleted without deletion of p16INK4a/ p14ARF. No correlation was observed between molecular studies and karyotype abnormalities as determined by conventional cytogenetics. Furthermore, no difference was found in the CR rate, CR duration, event-free survival, and overall survival in patients with homozygous gene deletions compared to patients with no deletions or loss of only one allele.
Faderl
S
S
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Kantarjian
H M
HM
Manshouri
T
T
Chan
C Y
CY
Pierce
S
S
Hays
K J
KJ
Cortes
J
J
Thomas
D
D
Estrov
Z
Z
Albitar
M
M
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D017353:Gene Deletion; D019942:Genes, p16 / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis; D011506:Proteins / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005819:Genetic Markers; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins