title: Crk-associated substrate lymphocyte type regulates myeloid cell motility and suppresses the progression of leukemia induced by p210Bcr/Abl.
abstract: The p210Bcr/Abl and p190Bcr/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 p190Bcr/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 p210Bcr/Abl, we generated Cas-L(-/-) p210Bcr/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(-/-) p210Bcr/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.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Seo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamoto
authors.forename: Masataka
authors.initials: M
authors.lastname: Takeshita
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sato
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kamikubo
authors.forename: Motoshi
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Noda
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D016313:Genes, abl; D006098:Granulocytes / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D017254:Leukemic Infiltration; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050719:Crk-Associated Substrate Protein; C505592:NEDD9 protein, mouse; D016044:Fusion Proteins, bcr-abl