Expansion of normal and leukemic human hematopoietic stem/progenitor cells requires rac-mediated interaction with stromal cells. Export

@article{citeulike:4845454, abstract = {OBJECTIVE: To determine the involvement of Rac signaling in self-renewal and expansion on bone marrow stroma of normal CD34+ cells vs leukemic CD34+ cells from acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: Rac signaling was modulated by retroviral introduction of Racl-N17, Racl-V12, or by using the Rac inhibitor NSC23766. In long-term MS5 cocultures (leukemic) expansion, migration, adhesion, and presence of stem/progenitor cells were monitored in both normal as well as leukemic CD34+ cells. RESULTS: Inhibition of Rac signaling impaired migration and adhesion of cord blood (CB) CD34+ cells on MS5 stroma. Long-term inhibition of Rac during a 5-week coculture period on stroma prevented association of hematopoietic progenitors with the bone marrow stromal cells and resulted in a dramatic decrease in the primitive stem cell frequency (long-term culture-initiating cell) in a dose-dependent manner. Many of these phenotypes were reversed in the presence of activated Racl-V12, including improved migration toward, and association with, MS5 cells. CD34+ AML cells were characterized by elevated levels of Rac activity (five of seven patients) and enhanced migration and adhesion to MS5 bone marrow stroma as compared to CB CD34+ cells. A dramatic decrease was observed in the formation of leukemic cobblestone area-forming cells as well as strongly diminished clonal expansion in the presence of the Rac inhibitor NSC23766. CONCLUSION: Our data indicate that Rac signal transduction is required for the maintenance and expansion of both normal as well as leukemic stem/progenitor cells by mediating their interaction with stromal cells.}, author = {Rozenveld-Geugien, M. and Baas, I. O. and van Gosliga, D. and Vellenga, E. and Schuringa, J. J.}, citeulike-article-id = {4845454}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/17577927}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=17577927}, issn = {0301-472X}, journal = {Experimental hematology}, keywords = {genetics, medicine, stem}, month = {May}, number = {5}, pages = {782--792}, posted-at = {2009-06-14 14:29:36}, priority = {2}, title = {Expansion of normal and leukemic human hematopoietic stem/progenitor cells requires rac-mediated interaction with stromal cells.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/17577927}, volume = {35}, year = {2007} }

TY - JOUR ID - citeulike:4845454 L3 - citeulike-article-id:4845454 N2 - OBJECTIVE: To determine the involvement of Rac signaling in self-renewal and expansion on bone marrow stroma of normal CD34+ cells vs leukemic CD34+ cells from acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: Rac signaling was modulated by retroviral introduction of Racl-N17, Racl-V12, or by using the Rac inhibitor NSC23766. In long-term MS5 cocultures (leukemic) expansion, migration, adhesion, and presence of stem/progenitor cells were monitored in both normal as well as leukemic CD34+ cells. RESULTS: Inhibition of Rac signaling impaired migration and adhesion of cord blood (CB) CD34+ cells on MS5 stroma. Long-term inhibition of Rac during a 5-week coculture period on stroma prevented association of hematopoietic progenitors with the bone marrow stromal cells and resulted in a dramatic decrease in the primitive stem cell frequency (long-term culture-initiating cell) in a dose-dependent manner. Many of these phenotypes were reversed in the presence of activated Racl-V12, including improved migration toward, and association with, MS5 cells. CD34+ AML cells were characterized by elevated levels of Rac activity (five of seven patients) and enhanced migration and adhesion to MS5 bone marrow stroma as compared to CB CD34+ cells. A dramatic decrease was observed in the formation of leukemic cobblestone area-forming cells as well as strongly diminished clonal expansion in the presence of the Rac inhibitor NSC23766. CONCLUSION: Our data indicate that Rac signal transduction is required for the maintenance and expansion of both normal as well as leukemic stem/progenitor cells by mediating their interaction with stromal cells. IS - 5 JF - Experimental hematology SN - 0301-472X EP - 792 TI - Expansion of normal and leukemic human hematopoietic stem/progenitor cells requires rac-mediated interaction with stromal cells. VL - 35 SP - 782 KW - genetics KW - medicine KW - stem AU - Rozenveld-Geugien, M AU - Baas, IO AU - van Gosliga, D AU - Vellenga, E AU - Schuringa, JJ PY - 2007/05// UR - http://view.ncbi.nlm.nih.gov/pubmed/17577927 ER -