Gain of MYC underlies recurrent trisomy of the MYC chromosome in acute promyelocytic leukemia.
Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukemia (AML). It has been hypothesized that gain of the MYC protooncogene is of central importance in trisomy 8, but the experimental data to support this are limited and controversial. In a mouse model of promyelocytic leukemia in which the MRP8 promoter drives expression of the PML-RARA fusion gene in myeloid cells, a Myc allele is gained in approximately two-thirds of cases as a result of trisomy for mouse chromosome 15. We used this model to test the idea that MYC underlies acquisition of trisomy in AML. We used a retroviral vector to drive expression of wild-type, hypermorphic, or hypomorphic MYC in bone marrow that expressed the PML-RARA transgene. MYC retroviruses cooperated in myeloid leukemogenesis and suppressed gain of chromosome 15. When the PML-RARA transgene was expressed in a Myc haploinsufficient background, we observed selection for increased copies of the wild-type Myc allele concomitant with leukemic transformation. In addition, we found that human myeloid leukemias with trisomy 8 have increased MYC. These data show that gain of MYC can contribute to the pathogenic effect of the most common trisomy of human AML.
Helen Diller Family Comprehensive Cancer Center and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Letetia
L
Jones
Guangwei
G
Wei
Sabina
S
Sevcikova
Vernon
V
Phan
Sachi
S
Jain
Angell
A
Shieh
Jasmine C Y
JC
Wong
Min
M
Li
Joshua
J
Dubansky
Mei Lin
ML
Maunakea
Rachel
R
Ochoa
George
G
Zhu
Thelma R
TR
Tennant
Kevin M
KM
Shannon
Scott W
SW
Lowe
Michelle M
MM
Le Beau
Scott C
SC
Kogan
D000818:Animals; D002478:Cells, Cultured; D002898:Chromosomes, Human, Pair 8; D004195:Disease Models, Animal; D016259:Genes, myc; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012008:Recurrence; D014314:Trisomy
D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein