Abstract 3938: MafB and ETS2 potentiate Notch signaling in T-ALL

Abstract

Abstract Despite the high frequency of activating Notch mutations in human T-cell acute lymphoblastic leukemia (T-ALL), these naturally occurring Notch1 mutant alleles fail to efficiently drive leukemia onset, indicating a requirement for collaborating events that potentiate the Notch oncogenic program. We performed an in vitro gain-of-function screen to identify gene products that enhanced the signaling strength of naturally occurring Notch mutants. Both MafB and ETS2 emerged as candidates that individually potentiated Notch signaling, and when co-expressed, they dramatically enhanced signaling strength comparable to the levels induced by MAML1, a core component of the Notch transcriptional complex. Knockdown of MafB in mouse T-ALL cell lines suppressed the expression of common Notch target genes, including cMyc and Hes1, and sustained knockdown of MafB expression impaired T-ALL cell growth in cell competition assays. Notably, MafB is sufficient to enhance the oncogenic potential of naturally occurring Notch mutants in vivo, by significantly accelerating T-ALL onset. Moreover, this enhanced Notch pathway activation required MafB-ETS2 interaction, and facilitated the recruitment of PCAF and p300. Although all primary human T-ALL samples that express MafB display an elevated Notch pathway signature, the T-ALL samples positive for high levels of MafB expression, exhibit low levels of Notch1 expression, further suggesting a role for MafB as an enhancer. These data present a novel mechanism for the enhancement of the oncogenic potential of weak Notch mutants in leukemia and introduce MafB as a potential therapeutic target in T-ALL. Note: This abstract was not presented at the meeting. Citation Format: Kostandin Pajcini, Lanwei Xu, Curtis Lee, Sara Cherry, Warren Pear. MafB and ETS2 potentiate Notch signaling in T-ALL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3938. doi:10.1158/1538-7445.AM2015-3938