Evidence map›Paper›PMID 40766713›Full record

ArticlebioRxiv : the preprint server for biology2025

Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity.

Rishi V Puram, Qiangzong Yin, YuhJong Liu, Justine C Rutter, Daniel Bondeson, Maria C Saberi, Lisa Miller, Michael Du, Khanh Nguyen, Donovan L Batzli and 18 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors.

Rishi V PuramBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Qiangzong YinBroad Institute of Harvard and MIT, Cambridge, MA, USA.
YuhJong LiuBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Justine C RutterDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Daniel BondesonBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Maria C SaberiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Lisa MillerBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Michael DuBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Khanh NguyenBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Donovan L BatzliBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Hilina B WoldemichaelBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Christian TägerInstitute for Experimental Internal Medicine, Otto-von-Guericke-Universität, Magdeburg, Germany.
Anna GoldsteinBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Ming Y ChuBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Qi GuoBroad Institute of Harvard and MIT, Cambridge, MA, USA.
D R ManiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Michael NaumannInstitute for Experimental Internal Medicine, Otto-von-Guericke-Universität, Magdeburg, Germany.
Melissa M RonanBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Matthew G ReesBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Blanche C IpBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Mustafa KocakBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Mikolaj SlabickiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
John G DoenchBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Jennifer A RothBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Steven A CarrBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Namrata D UdeshiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Jingyi WuBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Todd R GolubBroad Institute of Harvard and MIT, Cambridge, MA, USA.

Funding

Dana Farber/Harvard Cancer Consortium Career Development Program in Clinical OncologyK12CA087723 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI David Tsai Ting · 2002 to 2026
$17.9M
Training Program in Molecular HematologyT32HL116324 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI NANCY BERLINER · 2013 to 2026
$7.4M
Making cancer precision medicine real: bottlenecks and opportunitiesR35CA242457 · NCI · BROAD INSTITUTE, INC. · PI GOLUB, TODD R. · 2019 to 2025
$6.9M
Center of Excellence for High Throughput Proteogenomic CharacterizationU24CA270823 · NCI · BROAD INSTITUTE, INC. · PI STEVEN A CARR, MICHAEL A GILLETTE · 2022 to 2026
$5.3M
Proteogenomic Predictors of Recurrence in Non-small Cell Lung CancerU01CA271402 · NCI · WASHINGTON UNIVERSITY · PI STEVEN A CARR, MICHAEL A GILLETTE · 2022 to 2026
$5.0M
NCI NIH HHS K12 CA087723NCI NIH HHS R35 CA242457NCI NIH HHS U01 CA271402NCI NIH HHS U24 CA270823NHLBI NIH HHS T32 HL116324
6 · The paper itself

Abstract

The DNA-incorporating nucleoside analogs azacytidine (AZA) and decitabine (DEC) have clinical efficacy in blood cancers, yet the precise mechanism by which these agents kill cancer cells has remained unresolved - specifically, whether their anti-tumor activity arises from conventional DNA damage or DNA hypomethylation via DNA methyltransferase 1 (DNMT1) inhibition. This incomplete mechanistic understanding has limited their broader therapeutic application, particularly in solid tumors, where early clinical trials showed limited efficacy. Here, through the assessment of drug sensitivity in over 600 human cancer models and comparison to a non-DNA-damaging DNMT1 inhibitor (GSK-3685032), we establish DNA hypomethylation, rather than DNA damage, as the primary killing mechanism of AZA and DEC across diverse cancer types. In further support of an epigenetic killing mechanism, CRISPR drug modifier screens identified a core set of chromatin regulators, most notably the histone deubiquitinase USP48, as AZA and DEC protective factors. We show that USP48 is recruited to newly hypomethylated CpG islands and deubiquitinates non-canonical histones, establishing USP48 as a key molecular link between the two components of epigenetic gene regulation: DNA methylation and chromatin modification. Furthermore, loss of

Identifiers

PMID40766713
PMCPMC12324281

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.