NPM1 deletion is associated with gross chromosomal rearrangements in leukemia.
BACKGROUND
NPM1 gene at chromosome 5q35 is involved in recurrent translocations in leukemia and lymphoma. It also undergoes mutations in 60% of adult acute myeloid leukemia (AML) cases with normal karyotype. The incidence and significance of NPM1 deletion in human leukemia have not been elucidated.


RESULTS
Bone marrow samples from 145 patients with myelodysplastic syndromes (MDS) and AML were included in this study. Cytogenetically 43 cases had isolated 5q-, 84 cases had 5q- plus other changes and 18 cases had complex karyotype without 5q deletion. FISH and direct sequencing investigated the NPM1 gene. NPM1 deletion was an uncommon event in the "5q- syndrome" but occurred in over 40% of cases with high risk MDS/AML with complex karyotypes and 5q loss. It originated from large 5q chromosome deletions. Simultaneous exon 12 mutations were never found. NPM1 gene status was related to the pattern of complex cytogenetic aberrations. NPM1 haploinsufficiency was significantly associated with monosomies (p<0.001) and gross chromosomal rearrangements, i.e., markers, rings, and double minutes (p<0.001), while NPM1 disomy was associated with structural changes (p=0.013). Interestingly, in complex karyotypes with 5q- TP53 deletion and/or mutations are not specifically associated with NPM1 deletion.


CONCLUSIONS
NPM1/5q35 deletion is a consistent event in MDS/AML with a 5q-/-5 in complex karyotypes. NPM1 deletion and NPM1 exon 12 mutations appear to be mutually exclusive and are associated with two distinct cytogenetic subsets of MDS and AML.
La Starza
Roberta
R
Hematology, University of Perugia, Perugia, Italy.
Matteucci
Caterina
C
Gorello
Paolo
P
Brandimarte
Lucia
L
Pierini
Valentina
V
Crescenzi
Barbara
B
Nofrini
Valeria
V
Rosati
Roberto
R
Gottardi
Enrico
E
Saglio
Giuseppe
G
Santucci
Antonella
A
Berchicci
Laura
L
Arcioni
Francesco
F
Falini
Brunangelo
B
Martelli
Massimo Fabrizio
MF
Sambani
Constantina
C
Aventin
Anna
A
Mecucci
Cristina
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002648:Child; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D014178:Translocation, Genetic; D055815:Young Adult
C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin