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Independent but complementary studies from Vakoc and Stegmaier identify and characterize a role for ETV6 in counteracting the transcriptional activity of EWS-FLI1 during Ewing sarcoma development, which may be targeted for therapeutic benefits.

There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.

The N⁶-methyladenosine (m⁶A) modification in mRNAs, generated by the enzyme METTL3, controls normal human hematopoietic stem/progenitor cell differentiation and maintains the undifferentiated leukemic phenotype of human acute myeloid leukemia cells.

Here, the authors show that HDAC1 and HDAC2 genetically interact, with each paralog being synthetically lethal with hemizygous deletion of the other. Mechanistically, HDAC1/2 co-deficiency leads to degradation of the NuRD complex, decreased chromatin accessibility and aberrant enhancer-based interactions.

Two studies show that some cancers are driven by genetic changes in the NSD3 protein that alter its enzymatic activity. Biochemical and structural characterization hints at a route to pharmacological reversal.

Transcriptome-wide effects of gene knockouts are screened at the single-cell level by combining high-throughput, single-cell RNA-seq with lentiviral CRISPR libraries.

Acute myeloid leukemia (AML) cells require BRD9 to regulate MYC gene expression and prevent myeloid differentiation. Selective inhibition of BRD9 using a chemical probe that was validated using a resistant bromodomain-swap allele of BRD9 limits AML cell growth.

Comparative genomic analyses of primary tumors and metastases within individuals with pancreatic cancer have exposed the complex clonal dynamics that underlie the dissemination of cancer cells to distant sites. Recent studies implicate non-genetic mechanisms in this process, particularly fluctuations in chromatin states and metabolism, which can endow rare cells within a primary tumor with metastatic potential.

High levels of histone acetylation at rhabdomyosarcoma SEs, including SOX8, are detrimental to transcription via exclusion of RNA Pol II, but not BRD4, from phase condensates.

The intricate regulation of cell death pathways remains to be understood. Here the authors identify that PTPN23 functions as a cell death checkpoint to restrain apoptosis, necroptosis and pyroptosis via regulating the endosomal sorting of death receptors and Toll-like receptors.

BRD8 is identified as a specific epigenetic vulnerability for glioblastomas that harbour wild-type p53.

The POU2F3–OCA-T complex is the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft-cell-like small-cell lung cancer.

Combinatorial CRISPR screens can be utilized to identify genetic interactions and functional redundancies of multiple genes. Here, the authors benchmark ten digenic CRISPR technologies and identify novel Cas9 tracrRNA combinations that show superior performance.

Marker-based CRISPR screens in pancreatic cancer cells followed by functional validation highlight a role for MED12 in bridging ΔNp63 and components of the Mediator family. This interaction helps drive basal cell identity in pancreatic ductal adenocarcinoma.

The transcription factor oestrogen receptor alpha (ERα) has long been targeted for therapeutic benefit in cancer, but drug resistance can emerge through a multitude of mechanisms. A study now reveals how the ERα cistrome can become reprogrammed to confer resistance to tamoxifen in breast cancer.

SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57^Kip2.

Host defense against helminth infection is mediated by mucosal type 2 immunity. Using gain- and loss-of-function mouse models, and mouse intestinal organoids, Xiong et al. show that SIRT6 modulates tuft and goblet cell expansion in intestinal epithelium by activating STAT6 to maintain type 2 mucosal immunity in response to helminth infection.

A chemical probe BI-9321 for the PWWP1 domain of NSD3 and its inactive analog were identified. BI-9321 binds to the methyl-lysine binding site, reduces the association of NSD3 with chromatin and inhibits proliferation of acute myeloid leukemia cells.

Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage with an aggressive subtype caused by translocations involving PAX3- /PAX7-FOXO1 chimeric transcription factors. Here the authors show that the BRG1-containing BAF complex is overexpressed and acts largely independently of the PAX3-FOXO1 chimera on chromatin to result in a myogenic differentiation blockade in this malignancy.

The development of post-chemotherapy resistance is a significant issue in the management of AML. Here, Caiado et al. suggest that the issue might be circumvented via upfront combination with hypomethylating agents that shape the clonal dynamics and transcriptional landscape of relapsing AML

In leukemia, diverse fusion proteins involving the MLL gene can drive oncogenic activity. Here, the authors describe a dependency of MLL-leukemia cells on the methyltransferase SETD2 to maintain genomic integrity during leukemia initiation and maintenance.

Cancer drug targets are identified by CRISPR-based screens that knock out functional protein domains.

The efficiency of base editing is substantially increased by optimizing expression and nuclear localization of the editing enzymes.

The methyltransferase METTL3 promotes the leukaemic state in acute myeloid leukaemia (AML) by catalysing the m⁶A RNA modification through its recruitment on the transcription start sites of AML-associated genes.

BET bromodomain inhibitors are being explored as potential therapeutics in cancer; here, AML cells are shown to evade sensitivity to BET inhibition through rewiring the transcriptional regulation of BRD4 target genes such as MYC in a process that is facilitated by suppression of PRC2 and WNT signalling activation.

This Opinion, written by many leading experts in small cell lung cancer (SCLC) research, proposes a new model of SCLC subtypes defined by differential expression of four key transcription regulators. Such classification should help to focus and accelerate therapeutic research.