Project description:
Acute leukemias driven by genetic alteration in the MLL1 or NPM1 genes require the chromatin adapter protein Menin to sustain leukemogenic gene expression and self-renewal. Inhibitors of Menin are currently tested in clinical trials and show promise in patients with leukemia refractory to available therapies. Despite the efficacy of these novel class of drugs, acquired drug resistance limits the duration of clinical responses. Dr. Perner and his team have identified novel mutations in the gene coding for Menin that lead to weaker drug binding and ultimately resistance and disease relapse. The detailed characterization of the structural basis and molecular determinants of drug resistance in many patients now pave the way for improvements in diagnostic testing as well as the development of second-generation inhibitors with alternative target binding modes.
Publication:
Perner F., Stein E.M., Wenge D.V., Singh S., Kim J., Apazidis A., Rahnamoun H., Anand D., Marinaccio C., Hatton C., Wen Y., Stone R.M., Schaller D., Mowla S., Xiao W.,10, Gamlen H.A., Stonestrom A.J., Persaud S., Ener E., Cutler J.A., Doench J.G., McGeehan G.M., Volkamer A., Chodera J.D., Nowak R.P., Fischer E.S., Levine R.L., Armstrong S.A., Cai S.F. MEN1 mutations mediate clinical resistance to Menin inhibition. 2023. Nature.
Submitting the Paper of the Month:
Else Kröner-Fresenius-Stiftung is using the series “Paper of the Month” to report in an exemplary and hot-off-the-press style on the outstanding work being done by the scientists it supports. We regularly present publications which have recently appeared in especially renowned journals, have emerged from foundation funding and been given appropriate acknowledgment. This is done in the respective categories “Original Paper” and “Review”. In the case of each of these publications, the first author and/or senior author are being funded by the foundation.
We invite all project managers, fellowship recipients and members of graduate study programs to send their work in accordance with the stated criteria as proposal for Paper of the Month to Ms. Anne Asschenfeldt (a.asschenfeldt@ekfs.de).
