Konference: 2007 49th ASH Annual Meeting - účast ČR
Kategorie:
Maligní lymfomy a leukémie
Téma: Postery
Číslo abstraktu: 1130
Autoři: Tomas Stouka; Mgr. Karina Vargová, Ph.D.; Mgr. Juraj Kokavec; Mgr. Vít Pospíšil; Mgr. Nikola Čuřík, Ph.D.; Mgr. Pavel Burda, Ph.D.; Arthur I. Skoultchi, Ph.D.; Jiri Zavadil, Ph.D.
MicroRNAs are non-coding post-transcriptional regulators of gene
expression often dysregulated in human cancers including
hematological malignancies. MiR-155 is a putative oncogenic factor
found overexpressed in chronic lymphocytic leukemia (CLL) cells. We
have confirmed the increased levels of miR-155 in peripheral blood
lymphocytes in 12 patients with chronic lymphocytic leukemia (CLL)
compared to 11 normal controls, using quantitative PCR assay. Among
the predicted high-scoring hematopoietic target genes of miR-155 is
the ets-family transcription factor PU.1, a key regulator of
myelo-lymphoid lineage development. Using gene expression profiling
of CLL peripheral lymphocyte samples compared to normal controls,
we have determined significant downregulation of the PU.1 mRNA and
of additional numerous miR-155 targets previously reported to be
required for myelo-lymphoid differentiation, and of a set of gene
targets of PU.1-chromatin DNA interactions that we determined by
chromatin immunoprecipitation analyses. Functional pathway analysis
of the miR-155 targets downregulated in CLL patients suggest the
suppression of T-cell receptor pathway, TGF-b/Bmp, MAPK, Jak/Stat
and Wnt signaling and remodeling of actin cytoskeleton and
cell-matrix interactions, as well as the regulation of numerous
transcription regulators including c-FOS, c-MYC, MAFB and HDAC4.
Recent reports suggested a role of miR-155 in lymphocytic
differentiation, we have tested whether PU.1 may regulate
expression of its own regulator miR-155. We used two cell systems
expressing a transgene encoding PU.1 fused with the ligand binding
domain of the estrogen receptor, ER): 1) murine erythroleukemia
(MEL) cells (Rao 1997) and 2) PU.1 null hematopoietic progenitor
cells stably transfected with PU.1-ER (Walsh 2002). Using a miRNA
microarray assay we have identified a set of 21 miRNAs that are
modulated by PU.1. Indeed, miR-155 was among the upregulated
targets alongside a known PU.1 miR target miR-233. The direct
interaction between miR-155 promoter and PU.1 protein was confirmed
by chromatin immunoprecipitation in MEL cells. In summary, our data
suggests that increased miR-155 levels may contribute to CLL by
inhibiting PU.1 function and suppressing PU.1-mediated programs and
that in two independent conditional PU.1 cell systems PU.1 directly
binds miR-155 promoter and upregulates its expression suggesting
thus a mutual regulatory mechanism between PU.1 and miR-155.
Abstract #1130 appears in Blood, Volume 110, issue 11, November 16,
2007
Keywords: Chronic Lymphocytic Leukemia|PU.1|Molecular Markers
Disclosure: No relevant conflicts of interest to declare.
Saturday, December 8, 2007 5:30 PM
Session Info: Poster Session: CLL: Molecular Biology (5:30
p.m.-7:30 p.m.)
Datum přednesení příspěvku: 8. 12. 2007