T-cell acute lymphoblastic leukemia (T-ALL) is one of the most aggressive hematological cancers comprising 15% and 25% of pediatric and adult acute lymphoblastic leukemia cases, respectively. Although today T-ALL therapy has significantly improved, some patients still experience resistance to treatments and relapse. High prevalence of aberrant Notch1 activation and Notch3 expression in T-ALL makes Notch pathway one of the most important therapeutic targets in this disease. However, current Notch-targeted therapies in clinical developing are not selective, still produce limited anti-cancer effects and cause severe side effects hindering their therapeutic applicability. Thus, a detailed molecular dissection of Notch signal could unveil novel therapeutic alternatives with effective anti-leukemic potential and low toxicity. Besides Notch1 activating mutations occurring in more then 50% of T-ALL cases, the majority of T-ALL patients display up-regulation of Notch3 irrespectively to Notch3 gene mutations or rearrangements. However, machinery driving Notch3 overexpression in T-ALL is mostly undefined. Aim of our proposal is to decipher the molecular mechanisms controlling Notch3 signaling focusing on transcription factors and epigenetic modifiers that mediate its transcription in T-ALL cell contexts. A deep dissection of Notch3 regulation could reveal novel potential therapeutic targets relevant in T-ALL malignancy.
Given the prominent role of Notch signaling in physiological development of many tissues and in pathogenesis, chemoresistance and relapse of different human cancers, including T-ALL, in the last decade, many efforts have been paid to unveil molecular mechanisms priming Notch receptors activation or sustaining the strength and activity of the signaling [1]. However, less attention is paid to understand the upstream mechanisms regulating Notch receptor expression, particularly those involved in Notch3 transcriptional activation. Although, it is assumed that Notch3 is a target gene of Notch1, to date, it has not been clarified yet how its oncogenic expression/activation results to be aberrant even in T-ALL contexts lacking of Notch1 activation.
Despite evidence suggests that the epigenetic machinery drives Notch3 expression in different cell context, yet not much is known about the specific histone modifiers writing or erasing the chromatin status at its gene locus. Our proposal is designed to gain further additional mechanistic insights into Notch3 regulation with the aim to advance the understanding of distinct interplays between Notch receptors, transcriptional factors and histones modifiers relevant in Notch3 oncogenic activation in different subtype of T-ALL. In addition, given that modifying Notch3 expression in tumors exerts anticancer effects [2], it could be a promising option to further stimulate the development of novel and more effective Notch-targeted therapies in cancer to get new insights into the biology of Notch3 regulation at its transcriptional level. Moreover, although in the last decades several potential anti-Notch approaches have been proposed [3], actually, the most explored class of Notch blocking agents, gamma-secretase inhibitors (GSIs), is not selective for individual Notch receptors and often causes goblet cell metaplasia due to simultaneous inhibition of Notch1 and Notch2 in the gut [4]. Therefore, more restricted tissue distribution of Notch3 than Notch1 and Notch2 [5] and its not essential role for vitality and fertility observed in mice [6] promise that the identification of key factors sustaining its expression could drive the design of novel therapeutic strategies avoiding severe GSI-related side effects. Finally, supporting the potential safety for the selective therapeutic inhibition of Notch3 expression by targeting histone modifiers, treatments with the dual JMJD3/UTX small-molecule inhibitor GSKJ4 exert anti-leukemic effects in mice models of T-ALL without showing adverse effects in the intestine or in the hematopoietic system [7,8] and similarly, treatments with the catalytic inhibitor of CBP/p300 A-485 showed anti-tumor effects in prostate xenograft mice models without evident associate adverse effects, except for a very moderate weight loss that recovered rapidly upon completion of the treatment [9].
References:
1 Palermo, R., et al. Current molecular medicine 14, 34-44 (2014)
2 Aburjania, Z. et al. The oncologist, 2017-0677 (2018)
3 Bellavia, D., et al. Expert opinion on therapeutic targets 22, 331-342, (2018)
4 Vooijs, M., et al. Gastroenterology 141, 448-459, (2011)
5 Wu, J. et al. Trends in biochemical sciences 32, 477-485, (2007)
6 Krebs, L. T. et al. Genesis 37, 139-143, (2003)
7 Ntziachristos, P. et al. Nature 514, 513-517 (2014)
8 Benyoucef, A. et al. Genes & development 30, 508-521 (2016)
9 Lasko, L. M. et al. Nature 550, 128-132, (2017)