title: Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells.
abstract: Signals from the tumor microenvironment promote the migration, survival, and proliferation of chronic lymphocytic leukemia (CLL) cells. Rho GTPases control various signaling pathways downstream of microenvironmental cues. Here, we analyze the function of Rac1 in the motility and proliferation of CLL cells. We found decreased transcription of the Rac guanine nucleotide exchange factors Tiam1 and Vav1 in unstimulated peripheral blood CLL cells with almost complete loss of Tiam1 but increased transcription of the potential Rac antagonist RhoH. Consistently, stimulation of CLL cells with the chemokine CXCL12 induced RhoA but not Rac1 activation, whereas chemokine-induced CLL cell motility was Rac1-independent. Coculture of CLL cells with activated T cells induced their activation and subsequent proliferation. Here, Tiam1 expression was induced in the malignant cells in line with increased Ki-67 and c-Myc expression. Rac1 or Tiam1 knockdown using siRNA or treatment with the Tiam1/Rac inhibitor NSC-23766 attenuated c-Myc transcription. Furthermore, treatment of CLL cells with NSC-23766 reduced their proliferation. Rac inhibition also antagonized the chemoresistance of activated CLL cells toward fludarabine. Collectively, our data suggest a dynamic regulation of Rac1 function in the CLL microenvironment. Rac inhibition could be of clinical use by selectively interfering with CLL cell proliferation and chemoresistance.
authors: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Oncology, Hemostaseology, Infectiology, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria;
authors: Sebastian W
authors: SW
authors: Hofbauer
authors: Peter W
authors: PW
authors: Krenn
authors: Sylvia
authors: S
authors: Ganghammer
authors: Daniela
authors: D
authors: Asslaber
authors: Ulrike
authors: U
authors: Pichler
authors: Karin
authors: K
authors: Oberascher
authors: Reinhard
authors: R
authors: Henschler
authors: Michael
authors: M
authors: Wallner
authors: Hubert
authors: H
authors: Kerschbaum
authors: Richard
authors: R
authors: Greil
authors: Tanja N
authors: TN
authors: Hartmann
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D041681:NIH 3T3 Cells; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D020662:Guanine Nucleotide Exchange Factors; C487513:NSC 23766; D011743:Pyrimidines; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D020830:rac1 GTP-Binding Protein