RT Journal Article
SR Electronic
T1 MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP eaam6846
DO 10.1126/scisignal.aam6846
VO 10
IS 505
A1 Pajcini, Kostandin V.
A1 Xu, Lanwei
A1 Shao, Lijian
A1 Petrovic, Jelena
A1 Palasiewicz, Karol
A1 Ohtani, Yumi
A1 Bailis, Will
A1 Lee, Curtis
A1 Wertheim, Gerald B.
A1 Mani, Rajeswaran
A1 Muthusamy, Natarajan
A1 Li, Yunlei
A1 Meijerink, Jules P. P.
A1 Blacklow, Stephen C.
A1 Faryabi, Robert B.
A1 Cherry, Sara
A1 Pear, Warren S.
YR 2017
UL http://stke.sciencemag.org/content/10/505/eaam6846.abstract
AB T cell acute lymphoblastic leukemias (T-ALLs) are often caused by mutations in the gene encoding Notch1, which mediates cell-cell contact signaling in embryonic development and adult tissue maintenance. However, mice expressing these mutants frequently fail to develop T-ALL. Pajcini et al. found that the transcription factors MAFB and ETS2 increased the expression of Notch1 target genes in mouse and human T-ALL cells by recruiting histone acetyltransferases. Expressing MAFB enhanced the development of Notch1-mutant T-ALL in mice. Because Notch1 is critical for the maintenance of various healthy adult tissues, developing a way to inhibit MAFB or its interacting partners may be a more targeted therapy for leukemia patients.Activating mutations in the gene encoding the cell-cell contact signaling protein Notch1 are common in human T cell acute lymphoblastic leukemias (T-ALLs). However, expressing Notch1 mutant alleles in mice fails to efficiently induce the development of leukemia. We performed a gain-of-function screen to identify proteins that enhanced signaling by leukemia-associated Notch1 mutants. The transcription factors MAFB and ETS2 emerged as candidates that individually enhanced Notch1 signaling, and when coexpressed, they synergistically increased signaling to an extent similar to that induced by core components of the Notch transcriptional complex. In mouse models of T-ALL, MAFB enhanced leukemogenesis by the naturally occurring Notch1 mutants, decreased disease latency, and increased disease penetrance. Decreasing MAFB abundance in mouse and human T-ALL cells reduced the expression of Notch1 target genes, including MYC and HES1, and sustained MAFB knockdown impaired T-ALL growth in a competitive setting. MAFB bound to ETS2 and interacted with the acetyltransferases PCAF and P300, highlighting its importance in recruiting coactivators that enhance Notch1 signaling. Together, these data identify a mechanism for enhancing the oncogenic potential of weak Notch1 mutants in leukemia models, and they reveal the MAFB-ETS2 transcriptional axis as a potential therapeutic target in T-ALL.