Study of the molecular mechanisms sustaining Notch3 expression in T-cell Acute Lymphoblastic Leukemia

Anno
2018
Proponente Rocco Palermo - Ricercatore
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Abstract

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.

ERC
LS2_5, LS3_5, LS4_6
Keywords:
EPIGENETICA E REGOLAZIONE GENICA, CANCRO, BASI BIOLOGICHE DEL CANCRO

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