July 9, 2020

The Niche

Knoepfler lab stem cell blog

Tumorigenicity and Pluripotency teased apart? Not yet for Myc

Myc in cancer and IPSCs
Fig. 5 Nakagawa, et al. Myc in cancer and IPScs

A paper just came out in PNAS entitled “Promotion of direct reprogramming by transformation-deficient Myc“. The main thrust of this paper is that the tumorigenic and pluripotency-related functions of Myc could be separated. It focused primarily on the lesser studied LMyc.

The topic of the intertwined good (pluripotency) and bad (tumorigenicity) functions of Myc, addressed in this paper by Yamanaka’s group, is extremely important and interesting. However there are several key open questions that remain.

An important issue with this paper is the implication it makes that LMyc is transformation-deficient. While it is correct to say that LMyc appears less oncogenic than cMyc and NMyc, particularly in vitro, LMyc remains an important human oncogene. LMyc is linked with many human cancers, particularly lung cancer. Therefore, LMyc is not necessarily a safer alternative to cMyc or NMyc for use in producing or modifying stem cells that would ever be used in regenerative medicine. The FDA, for example, would not approve a regenerative medicine therapy for clinical trials that used iPS cells made with ANY form of any Myc genes. If they ever do, I will happily eat my hat.

It is fascinating that the authors found that any of the 3 main Myc’s reduced the % of colonies that were true iPS cell colonies. Why would that be? We don’t know yet.

But it’s important to note that the Mycs were so powerful in increasing the total number of colonies formed that the net result of adding any Myc to the iPS cell production process was still a striking increase in the number of true iPS cell colonies. While L-Myc seemed the best at producing the highest percentage of true iPS cell colonies, it was not statistically better than NMyc was at doing this, and N-Myc is a powerful oncogene.

So at least for now for Myc, its tumorigenicity and pluripotency-related functions have not been separated…not yet. I am a mixture of skeptical and hopeful that that might be possible.

Myc seems to defy “domestication” and appears intent upon remaining more wolf than friendly dog. Any approach that fully removes Myc’s tumorigenicity (an absolute requirement for its use in any therapy) is going to kill all of Myc’s functions.