TY  - JOUR
AU  - Jankovic, Maja
AU  - Poon, William Wl
AU  - Gonzales-Losada, Cristobal
AU  - Vazquez, Gabriela Galicia
AU  - Sharif-Askari, Bahram
AU  - Ding, Yi
AU  - Craplet-Desombre, Constance
AU  - Ilie, Alexandru
AU  - Shi, Jiantao
AU  - Wang, Yongie
AU  - Jayavelu, Ashok Kumar
AU  - Orthwein, Alexandre
AU  - Mercier, Francois Emile
TI  - The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia.
JO  - Blood advances
VL  - 8
IS  - 20
SN  - 2473-9529
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2024-01572
SP  - 5315-5329
PY  - 2024
N1  - Proteomics and Cancer Cell Signaling Group / 2024 Oct 22;8(20):5315-5329
AB  - For several decades, induction therapy with nucleoside analogs, in particular cytarabine (Ara-C) and, to a lesser extent, fludarabine, has been the standard of care for patients diagnosed with acute myeloid leukemia (AML). Still, the anti-tumor efficacy of nucleoside analogs is often limited by intrinsic and acquired drug resistance, thereby leading to poor therapeutic response and suboptimal clinical outcomes. Here, we used genome-wide CRISPR-based pharmacogenomic screening to map the genetic factors that modulate the response to nucleoside analogs in AML and identified the E3 ubiquitin ligase Herc1 as a key modulator of Ara-C response in the MLL/AF9 (MA) and the HOXA9/MEIS1 (HM) murine AML models both in vitro and in vivo. Loss of HERC1 enhanced nucleoside analog-induced cell death in both murine and human AML cell lines by compromising cell cycle progression. In-depth proteomic analysis and subsequent validation identified deoxycytidine kinase Dck as a novel target of Herc1 in MA and HM murine cells. We observed that HERC1 is overexpressed in AML compared to other cancer types and higher HERC1 expression is associated with shorter overall survival of patients with AML in the TCGA and BEAT-AML cohorts. Collectively, this study highlights the importance of HERC1 in the response of AML cells to nucleoside analogs, thereby establishing this E3 ubiquitin ligase as a novel predictive biomarker and potential therapeutic target for the treatment of AML.
LB  - PUB:(DE-HGF)16
C6  - pmid:39093953
DO  - DOI:10.1182/bloodadvances.2023011540
UR  - https://inrepo02.dkfz.de/record/292064
ER  -