title: Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia.
abstract: The tissue microenvironment in chronic lymphocytic leukemia (CLL) has an increasingly recognized role in disease progression, but the molecular mechanisms of cross talk between CLL cells and their microenvironment remain incompletely defined. Bone marrow stromal cells (BMSC) protect CLL cells from apoptosis in a contact-dependent fashion, and have been used for the identification of key pathways such as the CXCR4-CXCL12 axis. To further dissect the molecular impact of BMSC on survival and the molecular activation signature of CLL cells, we co-cultured CLL cells with different BMSC. Gene expression profiling of CLL cells revealed that the lymphoid proto-oncogene TCL1 was among the top genes upregulated in CLL cells by BMSC. TCL1 mRNA and protein upregulation by BMSC was paralleled by decreases of TCL1-interacting FOS/JUN, and confirmed by qRT-PCR, immunoblotting, immunoprecipitations, and flow cytometry. Stroma mediated increases in TCL1 were also associated with decreased levels of TCL1-regulatory micro-RNAs (miR-29b, miR-181b, miR-34b). These findings demonstrate that the microenvironment has a proactive role in the regulation of the known signaling enhancer and pro-survival molecule TCL1 in CLL. This provides a further rationale for therapeutically targeting the cross talk between CLL and BMSC.
authors.affiliation: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sivina
authors.forename: E
authors.initials: E
authors.lastname: Hartmann
authors.forename: E
authors.initials: E
authors.lastname: Vasyutina
authors.forename: J M
authors.initials: JM
authors.lastname: Boucas
authors.forename: A
authors.initials: A
authors.lastname: Breuer
authors.forename: M J
authors.initials: MJ
authors.lastname: Keating
authors.forename: W G
authors.initials: WG
authors.lastname: Wierda
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.forename: M
authors.initials: M
authors.lastname: Herling
authors.forename: J A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism; D002450:Cell Communication; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C000715470:MAS1 protein, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C090851:TCL1A protein, human; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D051057:Proto-Oncogene Proteins c-akt