BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia.
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 proliferation. In severe combined immunodeficient (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.
Ban
Kechen
K
Department of Pediatrics Research, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Gao
Yin
Y
Amin
Hesham M
HM
Howard
Adrienne
A
Miller
Claudia
C
Lin
Quan
Q
Leng
Xiaohong
X
Munsell
Mark
M
Bar-Eli
Menashe
M
Arlinghaus
Ralph B
RB
Chandra
Joya
J
D000818:Animals; D001549:Benzamides; D001752:Blast Crisis; D049109:Cell Proliferation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010879:Piperazines / Q000494:pharmacology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C494957:FYN protein, human; D016044:Fusion Proteins, bcr-abl; D051076:Proto-Oncogene Proteins c-fyn