Mention “sequestration” in the US and scientists cringe at the memories of past budget freezes. But recently, a talented team of researchers has put the term in a more positive light; by sequestering MYC proteins in iPSCs, they’ve helped mitigate cancer risks in regenerative medicine. Since their first development in 2006, induced pluripotent stem cells (iPSCs) have held promise to treat and even cure human diseases.
Tissue derived from iPSCs could, in principle, replace any differentiated tissue in our bodies. Thus, iPSCs-based therapies have great potential in regenerative medicine and are now approaching the clinic. But as with many benefits comes without a consequences, and iPSCs are no exception to this rule. A long-term risk of developing cancer remains a significant concern for the clinical application of iPSCs-based therapies.
Interestingly, a large part of this risk seems to be associated with the inclusion of MYC among the so-called Yamanaka factors, used to induce pluripotency. Therefore, improved reprogramming procedures that greatly reduce but don’t eliminate the risk of cancer, have been developed before. Fortunately, a team from the Memorial Sloan-Kettering Cancer Center in New York led by Hans-Guido Wendel, has developed a genetically engineered system based on the temporary inactivation of MYC, with the amazing ability to destroy aggressive iPSC-derived cancers while sparing healthy iPSC-derived tissues.
The team sought to take advantage of cancer’s “oncongene dependence” (Jain et al., 2002), setting their sights on the MYC proteins. More specifically, they introduced tamoxifen-inducible dominant-negative MYC constructs into human and murine iPSCc that were derived from fibroblasts and let them form tumors in mice. Then, they induced dominant-negative MYC expression by giving tamoxifen and compared tumor development to control mice. Here’s what they found:
- Cancer and normal tissues derived from iPSCs differentially depend on MYC
- MYC sustains tumor-specific metabolic and chromatin changes in iPSC-derived tumors
- Engineering iPSCs with dominant-negative MYC is useful in improving their therapeutic safety in as it can be used to:
o Help eliminate remaining iPSCs before/after engraftment
o Selectively target and destroy rapidly growing cancers, while sparing differentiated tissue
Read all the details at Cell Reports, September 2014.