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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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NEOPLASIA

Brief Report

BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia

Kechen Ban1, Yin Gao1, Hesham M. Amin2, Adrienne Howard1, Claudia Miller1, Quan Lin2, Xiaohong Leng3, Mark Munsell4, Menashe Bar-Eli5, Ralph B. Arlinghaus3, and Joya Chandra1

Departments of1 Pediatrics Research, 2 Hematopathology, 3 Molecular Pathology, 4 Quantitative Sciences, and 5 Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston

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.


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