RACK1 maintains mouse hematopoietic stem cells by directly binding to and stabilizing LDB1

Rbm5 sustains leukemia stem cells through a Myc-driven transcriptional circuitry.

Acute myeloid leukemia (AML) represents a type of malignant hematological disease that is usually caused by the dysregulated developmental program of leukemia stem cells (LSCs). Here, we report that an unappreciated RNA-binding protein, Rbm5, selectively promotes murine leukemogenesis, maintains LSC self-renewal in vivo, and is dispensable for normal hematopoiesis. Rbm5 is highly expressed in LSCs, and its deficiency results in specifically defective LSC function, along with inhibition of self-renewal gene expression and induction of myeloid differentiation. Multi-disciplinary mechanistic investigations further identified Myc as the major and direct transcriptional target of Rbm5 in primary leukemia cells. Moreover, RBM5 not only interacts with MYC but also maintains its protein levels, thereby sustaining the Myc downstream transcriptional network through its proper genome-wide occupancy. Forced expression of Myc sufficiently rescued the Rbm5-depleted LSC defects. Thus, our study demonstrates that Rbm5 regulates the AML LSC program through non-canonical transcriptional mechanisms, providing a strong rationale for targeting Rbm5 therapeutically. In Brief. Zhang et al. illustrate the role of Rbm5 in sustaining the self-renewal program in leukemia stem. cells (LSCs) primarily through the Myc transcriptional network. Specifically, Rbm5 loss results in a significant decrease in Myc protein levels, thereby disrupting. the Myc downstream transcriptional network in LSCs. Notably, this effect is specific to LSCs, as. normal hematopoietic stem cells (HSCs) do not exhibit such changes upon Rbm5 loss.

Prdm15 deficiency perturbs hematopoietic stem and progenitor cell homeostasis.

The maintenance of homeostasis in hematopoietic stem and progenitor cells (HSPCs) is essential for the proper development of the entire hematopoietic system. However, the mechanisms underlying this regulatory equilibrium remain elusive. Here, we report that Prdm15 deficiency in HSPCs induces the accumulation of immature hematopoietic stem cells in mice. A series of transplantation assays shows that these cells display impaired reconstitution capacity and competitive fitness, which are associated with abnormal differentiation trajectories and transcriptional alterations identified by single-cell RNA sequencing. Mechanistically, integrated multi-omics analyses including ATAC-seq and CUT&Tag sequencing of HSPCs indicate that Prdm15 deficiency induces significant transcriptional and epigenetic alterations, particularly affecting the methyltransferase KMT2C and altering H3K4me1 and H3K27ac modifications at the promoters of hematopoietic developmental genes. Collectively, our findings establish PRDM15 as a critical epigenetic regulator of HSPCs, offering valuable insights into the molecular mechanisms underlying hematopoietic homeostasis.

TAL1 is indispensable in ETV2-primed human endothelial cell fate determination

ETS variant transcription factor 2 (ETV2) serves as a foundational transcription factor for endothelial lineage specification. However, the lineage-specific cofactors that orchestrate with ETV2 during endothelial fate commitment remain elusive. Here, we demonstrate that ETV2 drives the rapid forward programming of human pluripotent stem cells (hPSCs) into endothelial cells (ECs) by direct remodeling of endothelial-specific enhancers. Crucially, we identify T cell acute lymphocytic leukemia protein 1 (TAL1), which is traditionally characterized as a hematopoietic regulator, as an indispensable cofactor for ETV2-mediated endothelial commitment. Distinct from its role in murine development, TAL1 deficiency in hPSCs not only aborts the endothelial program by impairing H3K27ac deposition at key enhancers but also triggers a profound lineage redirection toward a mesenchymal fate. Mechanistically, TAL1 physically interacts with ETV2 to recruit the p300, thereby facilitating a permissive chromatin environment for endothelial identity. By leveraging an hPSC-based differentiation model, our findings establish TAL1 as a master gatekeeper of human EC specification and provide a molecular blueprint for how ETV2-centric complexes synergistically govern human cell fate.

Locus-specific transposable element expression drives human hematopoietic stem cell disease pathophysiology

This study provides direct evidence that VEXAS-specific TE govern HSC clonal dominance, thereby uncovering a regulatory axis underlying HSC biology and disease mechanisms, opening a therapeutic strategy directed towards the repetitive genome.

can modulate TAL1 transcriptional activity through interaction with LMO2

Targeting the NuRD Component, CHD4, Impairs Foxp3+ Treg Cell Production and Function and Promotes Anti-Tumor Immunity

Little is known about why Foxp3⁺ regulatory T (Treg) cells require at least three HDAC1/HDAC2-containing chromatin-remodeling complexes (NuRD, Sin3 and CoREST), or whether selective disruption of these complexes can be exploited to enhance antitumor immunity. Here, we investigated the role of chromodomain helicase DNA- binding protein 4 (CHD4), the ATP-dependent remodeling subunit of the NuRD complex, in Treg biology. Conditional deletion of Chd4 in Foxp3⁺ Tregs resulted in severe systemic autoimmunity and early lethality, accompanied by reduced Foxp3 expression, impaired Treg suppressive function, and loss of Treg lineage stability. Transcriptomic analyses demonstrated that CHD4 deficiency closely phenocopied Hdac2 deletion, whereas quantitative proteomic analyses revealed that CHD4 assembles into highly conserved NuRD complexes in both Treg and conventional CD4⁺ T cells. These findings indicate that the selective dependence of Tregs on CHD4 does not arise from the formation of lineage-specific protein complexes but rather from the unique epigenetic program maintained by CHD4-containing chromatin-remodeling complexes that is required for Treg differentiation and stability. Using a novel cellular target-engagement platform, we identified CH41, a potent small-molecule inhibitor of CHD4 that recapitulated the effects of genetic CHD4 ablation on Treg function. Pharmacological inhibition of CHD4 impaired intratumoral Treg accumulation and function and significantly inhibited the growth of lung and hepatocellular carcinomas in immunocompetent, but not immunodeficient, mice, without inducing systemic autoimmunity. Collectively, our findings identify CHD4 as a critical epigenetic regulator of Treg lineage stability and establish pharmacological targeting of the CHD4/NuRD axis as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.