Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia.
Deletion of the long arm of chromosome 9, del(9q), is a recurring chromosomal aberration in acute myeloid leukemia (AML) that is frequently associated with t(8;21). The critical gene products affected by del(9q) are unknown but likely cooperate with the AML1/ETO fusion gene created by t(8;21) in leukemogenesis. In 43 AML samples with del(9q), we used high-density microsatellite markers to define the commonly deleted region (CDR) to less than 2.4 Mb. We found no homozygous loss at any locus tested. The CDR contains 7 known genes, FRMD3, UBQLN1, GKAP42, KIF27, HNRPK, SLC28A3, and NTRK2, and 4 novel genes, RASEF, C9orf103, C9orf64, and C9orf76. In addition, TLE1 and TLE4 are adjacent to the CDR. We performed a comprehensive mutational analysis of the coding regions of all these genes. No sequence variations absent in normal controls were seen in more than a single del(9q) AML sample. Expression of 7 of the 10 genes examined was significantly down-regulated in del(19q)AML as compared with the CD34-purified progenitors from normal individuals, a pattern distinct from that seen in AML samples with a normal karyotype. The results of our studies are consistent with a model of tumor suppression mediated by haploinsufficiency of critical genes in del(9q) AML.
Sweetser
David A
DA
Department of Pediatrics, Massachusetts General Hospital, 55 Fruit Street--Jackson 904, Boston, MA 02114, USA. dsweetser@partners.org
Peniket
Andrew J
AJ
Haaland
Christina
C
Blomberg
Adam A
AA
Zhang
Yuntian
Y
Zaidi
Syed Tanweer
ST
Dayyani
Farshid
F
Zhao
Zheng
Z
Heerema
Nyla A
NA
Boultwood
Jacqueline
J
Dewald
Gordon W
GW
Paietta
Elisabeth
E
Slovak
Marilyn L
ML
Willman
Cheryl L
CL
Wainscoat
James S
JS
Bernstein
Irwin D
ID
Daly
Sarah B
SB
D000208:Acute Disease; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9; D015331:Cohort Studies; D017931:DNA Primers; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation; D014178:Translocation, Genetic / Q000235:genetics
D017931:DNA Primers