Modur, V; Singh, N; Mohanty, V; Chung, E; Muhammad, B; Choi, K; Chen, X; Chetal, K; Ratner, N; Salomonis, N; Weirauch, MT; Waltz, S; Huang, G; Privette-Vinnedge, L; Park, J; Janssen, EM; Komuronr, K. Defective transcription elongation in a subset of cancers confers immunotherapy resistance. Nature Communications. 2018; 9(1).
Transcription elongation is a key point of inducible gene expression regulation. Dr. K. Kumorov’s group reports widespread transcription elongation defects in a high proportion of cancers that correlate with poor immunotherapy response, highlighting transcription elongation defects as potential routes for immune resistance.
Nayak, RC; Hegde, S; Althoff, MJ; Wellendorf, AM; Mohmoud, F; Perentesis, J; Reina-Campos, M; Reynaud, D; Zheng, Y; Diaz-Meco, MT; Moscat, J; Cancelas, JA. The signaling axis atypical protein kinase C lambdaiota-Satb2 mediates leukemic transformation of B-cell progenitors. Nature Communications. 2019; 10(1):707-723.e8.
Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. Dr. Cancelas led this work showing that genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. It implicates the aPKCλ/ι-SATB2 signaling cascade in leukemic BCR-ABL+ B-cell progenitor transformation.
Weng, Q; Wang, J; He, D; Cheng, Z; Zhang, F; Verma, R; Xu, L; Dong, X; Liao, Y; He, X; Potter, A; Zhang, L; Zhao, C; Xin, M; Zhou, Q; Aronow, BJ; Blackshear, PJ; Rich, JN; He, Q; Zhou, W; Suva, ML; Waclaw, RR; Potter, SS; Yu, G; Lu, QR. Single-Cell Transcriptomics Uncovers Glial Progenitor Diversity and Cell Fate Determinants during Development and Gliomagenesis. Cell Stem Cell. 2019; 24(5).
By applying lineage-targeted single-cell transcriptomics, Dr. R. Lu lab uncovered an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Their study resolved the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlighted Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.
Hall, A; Choi, K; Liu, W; Rose, J; Zhao, C; Yu, Y; Na, Y; Cai, Y; Coover, RA; Lin, Y; Dombi, E; Kim, M; Levanon, D; Groner, Y; Boscolo, E; Pan, D; Liu, PP; Lu, QR; Ratner, N; Huang, G; Wu, J. RUNX represses Pmp22 to drive neurofibromagenesis. Science advances. 2019; 5(4).
Patients with neurofibromatosis type 1 are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. Dr. J. Wu led a study that showed dual genetic deletion of Runx1 and Runx3 in Schwann cells and precursors delayed neurofibromagenesis and prolonged mouse survival. The study reveals that targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.
Jayavaradhan, R; Pillis, DM; Goodman, M; Zhang, F; Zhang, Y; Andreassen, PR; Malik, P. CRISPR-Cas9 fusion to dominant-negative 53BP1 enhances HDR and inhibits NHEJ specifically at Cas9 target sites.. Nature Communications. 2019; 10(1).
Global inhibition of NHEJ factors has been one strategy to improve CRISPR-Cas9 mediated homology driven repair. Drs. P. Malik and P. Andreasson labs reported a novel approach by fusing a dominant-negative mutant of 53BP1 to Cas9 to enhance homology driven repair frequency, reduce NHEJ specifically at the Cas9 cut sites, and reduce the toxicity associated with global NHEJ inhibition