Back from a relaxing stay-cation as well as ASCO meeting--
The June 2010 issue of Molecular Systems Biology has a fascinating study identifying MYB and FOXM1 as "master regulators" of germinal center proliferation in lymph nodes. Why should we as pathologists care about this?
What piqued my curiosity here was a connection with my previous post summarizing what I learned at USCAP on the molecular pathology of diffuse large B-cell lymphoma (DLBCL) regarding dysregulated genes in DLBCL (including MYC) and identification of three gene expression subgroups, including the "germinal center B-cell-like" group.
The authors use some fascinating and powerful techniques around a systems biology approach to find master regulator genes controlling specific cellular processes (in this case, germinal center B-cell proliferation) as well as transcriptional regulation of protein complexes whose regulation whose availability must be regulated in a context-dependent manner.
The authors developed is an interaction network specific to human B cells (called the human B-cell interactome, HBCI) by reverse-engineering of transcriptional and post-translational interactions in mature human B cells from a diverse collection of 254 B-cell gene expression profiles derived from normal and malignant mature B cells (Lefebvre et al, 2007). They further integrated evidence from experimental assays, databases, and literature data mining, filtered by context-specific criteria, using an established evidence integration algorithm. Then, they used a novel algorithm, the Master Regulator Interference Analysis or MARINa, to interrogate the HBCI to discover MRs of key genetic programs in the germinal center (GC) reaction of antigen-mediated immune response, that is, normal progression through the GC.
They identified MYB and FOXM1 as "master regulators" of GC B cells since 80% of the genes jointly regulated by these transcription factors are activated in the GC. They also showed that MYB is a transcriptional activator of FOXM1 suggesting that they form a "feed-forward" loop involved in a synergistic activation of a large subset of GC-specific genes. I don't quite understand their use of the term "feed-forward" loop here--my understanding is that a feed-forward loop is when the anticipated future effect (which hasn't yet happened) triggers the cause in the present (which would otherwise have not have happened). An example is when there is a rumored or predicted shortage of a commodity, which leads to hoarding in anticipation of the shortage, which in turn causes a shortage to occur. It seems that this should be called a reinforcing feedback loop but whatever.
But they also validated that common MYB/FOXM1 targets were affected by silencing either MYB or FOXM1 using gene expression profiling. Specifically, they showed that downstream targets and other MRs are bound by MYB and FOXM1 in their promotor regions after MYB or FOXM1 silencing. Moreover, silencing of MYB and FOXM1 showed a decreased in proliferating cells in GCs and an increase in apoptotic cells. They further examined specific targets involved in the formation of a protein complex predicted by their model and found that about half of the MYB/FOXM1 targets cluster within a complex including novel interactions with pre-replication and mitotic proteins. They found that two mitotic kinases inferred in the complex, BUBR1 and AURKA, physically interact with MCM3 which are all direct targets of MYB and FOXM1.
My summary doesn't do justice to this paper (due to my own shortcomings in understanding) but if you're interested in lymphomas and/or systems biology, this is well-worth a read.