Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia.
The promyelocytic leukemia (PML) tumor suppressor of acute promyelocytic leukemia (APL) is essential for a number of proapoptotic and growth-suppressive pathways as well as for the activity of differentiating agents such as retinoic acid (RA). In human APL, the dose of PML is reduced to heterozygosity given that one allele is involved in the chromosomal translocation while the status of the remaining PML allele is unknown. We have therefore used single-strand conformational polymorphism (SSCP) and sequencing analysis to screen DNA from APL patients for mutations at the PML locus. We identified DNA sequence variations resulting in a truncated PML protein in APL cases that displayed RA resistance and a very poor prognosis. Mutation analysis also led to the identification of aberrant PML sequence variations in other hematopoietic malignancies. Complete functional loss of PML is therefore selected by the APL phenotype and associates with poor prognosis and RA unresponsiveness.
Gurrieri
Carmela
C
Molecular Biology Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
Nafa
Khedoudja
K
Merghoub
Taha
T
Bernardi
Rosa
R
Capodieci
Paola
P
Biondi
Andrea
A
Nimer
Stephen
S
Douer
Dan
D
Cordon-Cardo
Carlos
C
Gallagher
Robert
R
Pandolfi
Pier Paolo
PP
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D018807:Polymorphism, Single-Stranded Conformational; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000235:genetics*; D014212:Tretinoin / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin