TY - JOUR
T1 - BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia
AU - Ban, Kechen
AU - Gao, Yin
AU - Amin, Hesham M.
AU - Howard, Adrienne
AU - Miller, Claudia
AU - Lin, Quan
AU - Leng, Xiaohong
AU - Munsell, Mark
AU - Bar-Eli, Menashe
AU - Arlinghaus, Ralph B.
AU - Chandra, Joya
PY - 2008/3/1
Y1 - 2008/3/1
N2 - Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell prolif-eration. In severe combined immunodefi- cient (SCID) mice injected with Fyn shRNA-expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.
AB - Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell prolif-eration. In severe combined immunodefi- cient (SCID) mice injected with Fyn shRNA-expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.
UR - http://www.scopus.com/inward/record.url?scp=41949101422&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41949101422&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-05-091769
DO - 10.1182/blood-2007-05-091769
M3 - Article
C2 - 18180382
AN - SCOPUS:41949101422
SN - 0006-4971
VL - 111
SP - 2904
EP - 2908
JO - Blood
JF - Blood
IS - 5
ER -