Low p14ARF expression in de novo acute myeloid leukemia with normal karyotype is associated with poor survival.
The p14ARF protein activates the p53 tumor suppressor by binding to and inhibiting its negative regulator HDM-2. We have studied the prognostic impact of p14ARF in acute myeloid leukemia (AML). Leukemic cells from 57 adult patients with normal karyotype de novo AML were analyzed for p14ARF mRNA expression level using real-time polymerase chain reaction (RT-PCR). We also tested the effect of conventional anti-leukemic drugs and the mutant p53-targeting small molecule PRIMA-1 in vitro. Patients whose cells expressed more p14ARF mRNA than the 75th percentile (0.26) had significantly better survival compared with those expressing lower levels, 61 vs. 30% 3-year survival (p = 0.046). The difference remained significant also when NPM1/FLT3 status was considered. The mean effects of all the tested conventional anti-leukemic drugs were greater in leukemic cell samples expressing p14ARF mRNA >or= 0.26, but the differences were not statistically significant. In contrast, PRIMA-1 had a significantly greater effect on leukemic cell samples with low levels of p14ARF mRNA. We conclude that low levels of p14ARF mRNA in leukemic cells from patients with normal karyotype AML is associated with poor prognosis. Treatment with drugs targeting p53 may be a future possibility to improve outcome for these patients.
Paul
Esbjörn
E
Department of Medicine and Haematology, Karolinska University Hospital, Stockholm, Sweden.
Paul
Esbjörn
E
Uggla
Bertil
B
Deneberg
Stefan
S
Bengtzen
Sofia
S
Hermansson
Monica
M
Dahlman
Ingrid
I
Rosenquist
Richard
R
Wiman
Klas G
KG
Nahi
Hareth
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D016019:Survival Analysis; D014184:Transplantation, Homologous; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D055815:Young Adult
C000716967:NPM1 protein, human; D025803:Tumor Suppressor Protein p14ARF; D000090243:Nucleophosmin