MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia

Kostandin V. Pajcini, Lanwei Xu, Lijian Shao, Jelena Petrovic, Karol Palasiewicz, Yumi Ohtani, Will Bailis, Curtis Lee, Gerald B. Wertheim, Rajeswaran Mani, Natarajan Musuthamy, Yunlei Li, Jules P.P. Meijerink, Stephen C. Blacklow, Robert B. Faryabi, Sara Cherry, Warren S. Pear

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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, andwhen 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.

Original languageEnglish (US)
Article numberaam6846
JournalScience signaling
Volume10
Issue number505
DOIs
StatePublished - Nov 14 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this