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TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells

Truong, Peter ; Shen, Sylvie ; Joshi, Swapna ; Islam, Md Imtiazul ; Zhong, Ling ; Raftery, Mark J. ; Afrasiabi, Ali ; Alinejad-Rokny, Hamid ; Nguyen, Mary and Zou, Xiaoheng , et al. (2024) In Nature Communications 15(1).
Abstract

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy... (More)

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
issue
1
article number
7360
publisher
Nature Publishing Group
external identifiers
  • scopus:85202612159
  • pmid:39198401
ISSN
2041-1723
DOI
10.1038/s41467-024-51646-6
language
English
LU publication?
yes
id
9d34c48f-9ec3-4844-95c1-94d04751bb5e
date added to LUP
2025-01-08 11:32:16
date last changed
2025-07-10 16:06:02
@article{9d34c48f-9ec3-4844-95c1-94d04751bb5e,
  abstract     = {{<p>Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.</p>}},
  author       = {{Truong, Peter and Shen, Sylvie and Joshi, Swapna and Islam, Md Imtiazul and Zhong, Ling and Raftery, Mark J. and Afrasiabi, Ali and Alinejad-Rokny, Hamid and Nguyen, Mary and Zou, Xiaoheng and Bhuyan, Golam Sarower and Sarowar, Chowdhury H. and Ghodousi, Elaheh S. and Stonehouse, Olivia and Mohamed, Sara and Toscan, Cara E. and Connerty, Patrick and Kakadia, Purvi M. and Bohlander, Stefan K. and Michie, Katharine A. and Larsson, Jonas and Lock, Richard B. and Walkley, Carl R. and Thoms, Julie A.I. and Jolly, Christopher J. and Pimanda, John E.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-51646-6}},
  doi          = {{10.1038/s41467-024-51646-6}},
  volume       = {{15}},
  year         = {{2024}},
}