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.

Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia.

PANDOLFI DE RINALDIS, Pier Paolo
2004-01-01

Abstract

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.
2004
103
2358
2362
http://dx.doi.org/10.1182/blood-2003-07-2200
Animals; Antineoplastic Agents; Cells; Cultured; Child; DNA Mutational Analysis; Drug Resistance; Neoplasm; Fibroblasts; Genes; Tumor Suppressor; Humans; Leukemia; Promyelocytic; Acute; Mice; Neoplasm Proteins; Nuclear Proteins; Polymorphism; Single-Stranded Conformational; Transcription Factors; Tretinoin; Tumor Suppressor Proteins
C. Gurrieri;K. Nafa;T. Merghoub;R. Bernardi;P. Capodieci;A. Biondi;S. Nimer;D. Douer;C. Cordon-Cardo;R. Gallagher;P. P. Pandolfi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/63276
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