title: RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans.
abstract: Trafficking of B-cell chronic lymphocytic leukemia (CLL) cells to the bone marrow and interaction with supporting stromal cells mediates important survival and proliferation signals. Previous studies have demonstrated that deletion of Rhoh led to a delayed disease onset in a murine model of CLL. Here we assessed the impact of RhoH on homing, migration, and cell-contact dependent interactions of CLL cells. Rhoh(-/-) CLL cells exhibited reduced marrow homing and subsequent engraftment. In vitro migration toward the chemokines CXCL12 and CXCL13 and cell-cell interactions between Rhoh(-/-) CLL cells and the supporting microenvironment was reduced. In the absence of RhoH the distribution of phosphorylated focal adhesion kinase, a protein known to coordinate activation of the Rho GTPases RhoA and Rac, appeared less polarized in chemokine-stimulated Rhoh(-/-) CLL cells, and activation and localization of RhoA and Rac was dysregulated leading to defective integrin function. These findings in the Rhoh(-/-) CLL cells were subsequently demonstrated to closely resemble changes in GTPase activation observed in human CLL samples after in vitro and in vivo treatment with lenalidomide, an agent with known influence on microenvironment protection, and suggest that RhoH plays a critical role in prosurvival CLL cell-cell and cell-microenvironment interactions with this agent.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Anja
authors.initials: A
authors.lastname: Troeger
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Jenna
authors.initials: J
authors.lastname: Wood
authors.forename: William G
authors.initials: WG
authors.lastname: Blum
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology; D054382:Chemokine CXCL13 / Q000378:metabolism / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059016:Tumor Microenvironment / Q000235:genetics* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; C447841:RhoH protein, human; C496930:RhoH protein, mouse; D014157:Transcription Factors; D020741:rho GTP-Binding Proteins