Open AccessCrk‐associated substrate lymphocyte type regulates myeloid cell motility and suppresses the progression of leukemia induced by p210 Bcr/Abl
Author(s) -
Seo Sachiko,
Nakamoto Tetsuya,
Takeshita Masataka,
Lu Jun,
Sato Tomohiko,
Suzuki Takahiro,
Kamikubo Yasuhiko,
Ichikawa Motoshi,
Noda Masaki,
Ogawa Seishi,
Honda Hiroaki,
Oda Hideaki,
Kurokawa Mineo
Publication year - 2011
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02066.x
Subject(s) - chronic myelogenous leukemia , myeloid leukemia , cancer research , biology , population , breakpoint cluster region , leukemia , adapter molecule crk , myeloid , abl , immunology , tyrosine kinase , medicine , microbiology and biotechnology , signal transduction , signal transducing adaptor protein , receptor , biochemistry , environmental health
The p210 Bcr/Abl and p190 Bcr/Abl fusion oncoproteins are known to cause chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Bcr/Abl phosphorylates several proteins that can lead to leukemogenesis. Crk‐associated substrate lymphocyte type (Cas‐L)/human enhancer of filamentation‐1 (HEF1)/neural precursor cell expressed, developmentally down‐regulated 9 (NEDD9) is an adapter protein at focal adhesions known to be associated with solid tumor metastasis. Crk‐associated substrate lymphocyte type has also been reported to be tyrosine phosphorylated by p190 Bcr/Abl . We demonstrated that Cas‐L was expressed in murine granulocytes, as well as in lymphocytes, and that Cas‐L‐deficient ( Cas‐L −/− ) granulocytes had increased migratory activity and decreased adhesiveness. To examine whether Cas‐L was involved in leukemogenesis by p210 Bcr/Abl , we generated Cas‐L −/− p210 Bcr/Abl transgenic mice. The mice displayed early development of myeloproliferative neoplasm seen in the chronic phase of CML, which resulted in the early death of the mice. Pathologically, increased infiltration of myeloid cells into several tissues was detected in the absence of Cas‐L. In a hematopoietic reconstitution assay, Cas‐L −/− p210 Bcr/Abl transgenic cells showed a low population in the spleen, although only their myeloid cell population was normal. Thus, Cas‐L seems to regulate the progression of CML in a negative way, presumably by attenuating extramedullary hyperplasia. ( Cancer Sci 2011; 102: 2109–2117)