A new year for new science and a new science publishing model: Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia
Past year has certainly been anything but ordinary. While managing the pandemic, we also continued research on how diverse forms of acute myeloid leukemias, caused by different oncogenes, may co-opt shared molecular mechanisms. In work, initially led by Lauren (Marek) Forbes, and then by Sumiko Takao and Masahiro Uni, we found that definition of leukemia gene expression mechanisms can reveal general principles of cancer gene control and offer a pharmacologic strategy for its therapeutic reprogramming.
We posted the original manuscript “Therapeutic remodeling of CBP transcription factor complex controls oncogenic gene expression in acute myeloid leukemia” as a bioRxiv preprint during the pause in research activities caused by the COVID-19 surge in New York City in spring of 2020.
By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB in AML cells, we found that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. We proposed that convergently organized transcription factor complexes in AML cells control oncogenic gene expression programs. We still needed to prove experimentally that this model explained aberrant gene expression in diverse forms of AML.
So while we continued work, we tried a new form of scientific publishing, by submitting the preprint for peer review via Review Commons. The reviewers suggested many experiments, all of which either served to prove the proposed mechanism or clarify its presentation. You can read the Review Commons reviews of the original manuscript and our responses at bioRxiv.
This “publish, then review” model of publishing was recently endorsed at eLife, which will use it as its standard process starting this year.
With additional experiments, we have now found that the oncogenic functions of MYB are mediated by its aberrant assembly with LYL1, E2A, C/EBP, LMO2 and SATB1 factors. They are organized convergently in diverse AML subtypes, and in part associated with their inappropriate co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and redistribution of CBP/P300 with alternative factors such as RUNX1 to induce differentiation and apoptosis. Aberrant assembly and sequestration of MYB:CBP/P300 provide a unifying mechanism of oncogenic gene expression. This defines a strategy for their pharmacologic reprogramming and targeting for leukemias and other cancers caused by dysregulated gene control. Read the published paper at eLife, with all data openly available at Zenodo, and explanation at MSKCC News.
We anticipate that future development of clinical-grade MYB inhibitors will make it possible to test this new therapeutic strategy in clinical trials for patients with blood cancers and many other MYB-dependent malignancies. And we hope that new forms of scientific publishing will make science more rigorous, more inclusive, and more enjoyable.