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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2904-2908.
Prepublished online as a Blood First Edition Paper on January 7, 2008; DOI 10.1182/blood-2007-05-091769.
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Submitted May 23, 2007
Accepted December 16, 2007
BCR-ABL1 mediates upregulation of Fyn in chronic myelogenous leukemia
Kechen Ban, Yin Gao, Hesham M. Amin, Adrienne Howard, Claudia Miller, Quan Lin, Xiaohong Leng, Mark Munsell, Menashe Bar-Eli, Ralph B. Arlinghaus, and Joya Chandra*
Department of Pediatrics Research, U.T. M.D. Anderson Cancer Center, Houston, TX, United States
Department of Hematopathology, U.T. M.D. Anderson Cancer Center, Houston, TX, United States
Department of Molecular Pathology, U.T. M.D. Anderson Cancer Center, Houston, TX, United States
Department of Quantitative Sciences, U.T. M.D. Anderson Cancer Center, Houston, TX, United States
Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: jchandra{at}mdanderson.org.
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 upregulation, 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 as compared to chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an upregulation 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 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.
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