Expression profile of CREB knockdown in myeloid leukemia cells.
BACKGROUND
The cAMP Response Element Binding Protein, CREB, is a transcription factor that regulates cell proliferation, differentiation, and survival in several model systems, including neuronal and hematopoietic cells. We demonstrated that CREB is overexpressed in acute myeloid and leukemia cells compared to normal hematopoietic stem cells. CREB knockdown inhibits leukemic cell proliferation in vitro and in vivo, but does not affect long-term hematopoietic reconstitution.


METHODS
To understand downstream pathways regulating CREB, we performed expression profiling with RNA from the K562 myeloid leukemia cell line transduced with CREB shRNA.


RESULTS
By combining our expression data from CREB knockdown cells with prior ChIP data on CREB binding we were able to identify a list of putative CREB regulated genes. We performed extensive analyses on the top genes in this list as high confidence CREB targets. We found that this list is enriched for genes involved in cancer, and unexpectedly, highly enriched for histone genes. Furthermore, histone genes regulated by CREB were more likely to be specifically expressed in hematopoietic lineages. Decreased expression of specific histone genes was validated in K562, TF-1, and primary AML cells transduced with CREB shRNA.


CONCLUSIONS
We have identified a high confidence list of CREB targets in K562 cells. These genes allow us to begin to understand the mechanisms by which CREB contributes to acute leukemia. We speculate that regulation of histone genes may play an important role by possibly altering the regulation of DNA replication during the cell cycle.
Pellegrini
Matteo
M
Department of Molecular, Cellular, and Developmental Biology, University of California, Los Angeles, USA. matteop@mcdb.ucla.edu
Cheng
Jerry C
JC
Voutila
Jon
J
Judelson
Dejah
D
Taylor
Julie
J
Nelson
Stanley F
SF
Sakamoto
Kathleen M
KM
D002460:Cell Line; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D018816:Genes, cdc; D006657:Histones / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism*; D020218:Response Elements
D017362:Cyclic AMP Response Element-Binding Protein; D006657:Histones
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