Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis

Clifford A. Lowell, Maho Niwa, Philippe Soriano, Harold E. Varmus

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100 Scopus citations


Expression of the Src-family kinases-Src, Hck, and Fgr-increases dramatically during myeloid cell development. Src-deficient mice exhibit functional abnormalities in only one myeloid cell type, the osteoclast, resulting in impaired bone remodeling and osteopetrosis, while hck(-/-) or fgr(-/-) mice have few and subtle myeloid cell deficiencies. To determine whether these limited phenotypes are due to the coexpression of multiple Src- family kinases with overlapping functions, we have intercrossed src(-/-) mice to hck(-/-) and fgr(-/-) mutants to produce double mutants. Two thirds of hck(-/-)src(-/-) double mutants die at birth; surviving animals develop a severe form of osteopetrosis, resulting in extreme levels of splenic extramedullary hematopoiesis, anemia, and leukopenia. These hematopoietic defects are caused by abnormalities in the bone marrow environment because hck(-/-)src(-/-) mutant stem cells reconstitute a normal hematopoietic system in irradiated wild-type mice. In contrast, fgr(-/-)src(-/-) double mutants have no defects beyond those observed in src(-/-) animals. Cultured normal murine osteoclasts express abundant amounts of Src, Hck, and Fgr and Hck levels are increased in src(-/-) osteoclasts. These observations suggest that Hck and Src serve partially overlapping functions in osteoclasts and that the expression of Hck in src(-/-) osteoclasts ameliorates their functional defects.

Original languageEnglish
Pages (from-to)1780-1792
Number of pages13
Issue number5
StatePublished - 1 Mar 1996


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