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

Transcriptional Control as a Therapeutic Strategy in Acute Myeloid Leukemia

: Acute myeloid leukemia (AML) is driven by dysregulated transcription factors (TFs) that disrupt hematopoietic differentiation, promote leukemic self-renewal, and confer therapy resistance. Key TFs including C/EBP α , PU.1, RUNX1, GATA2, EVI1, PML-RAR α fusion protein, p53, c-Myc and ERG are altered through mutations, chromosomal rearrangements, and epigenetic remodeling, rewiring transcriptional circuits that converge on oncogenic pathways such as Wnt/ β -catenin, NF-κ B, and JAK/STAT3. Although TFs were historically considered “undruggable” due to their flat protein–protein interaction interfaces and lack of enzymatic pockets, recent advances have increasingly demonstrated their clinical tractability. The menin inhibitors revumenib and ziftomenib, which disrupt the Menin– KMT2A complex to suppress HOXA/MEIS1-driven transcription, have received FDA approval for relapsed or refractory NPM1-mutant AML, with revumenib also approved for KMT2A-rearranged acute leukemia. While these agents target a transcriptional regulatory complex rather than TFs directly, their clinical success highlights the therapeutic potential of modulating transcriptional regulatory networks and encourages the development of future therapies targeting TFs and their associated regulatory machinery. Additional strategies include reactivation of tumor suppressor pathways through p53-targeting agents, disruption of aberrant CBF β –RUNX1 signaling, inhibition of FOXM1 and NF-κ B, and epigenetic modulation through DOT1L, LSD1, and HDAC inhibitors. Emerging technologies are further expanding the druggable space: PROTACs and molecular glues enable event-driven degradation of previously intractable targets such as TAF1 and GSPT1, while artificial intelligence and graph-based machine learning facilitate identification of novel TF cascade vulnerabilities. However, durable clinical translation remains constrained by acquired resistance through MEN1 mutations and p300-mediated transcriptional remodeling, off-target hematopoietic toxicity, differentiation syndrome, transcriptional plasticity, and delivery challenges within the bone marrow microenvironment. This review provides a comprehensive synthesis of TF dysregulation mechanisms, genotype-specific targeting strategies linking molecular subtype to therapeutic approach, clinical trial outcomes, and emerging drug design technologies, offering a translational framework to guide the development of next-generation TF-targeted therapies in AML.

SETD5 regulates leukemic initiation and infiltration in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by aberrant epigenetic regulation. Although SET domain-containing 5 (SETD5) is structurally classified as a member of the histone methyltransferase family, it lacks canonical methyltransferase activity and functions primarily through nonenzymatic mechanisms. While recognized as a modulator in normal hematopoiesis, the role of SETD5 in T-ALL remains undefined. Here, we show that SETD5 contributes to efficient T-ALL initiation and progression in the models examined. Using ICN1-driven murine T-ALL models (Vav-Cre;Setd5fl/fl and Mx1-Cre;Setd5fl/fl), we show that genetic ablation of Setd5 impairs efficient leukemia initiation. In transplantation assays, Setd5 depletion reduces leukemia burden, prolongs survival, and impairs leukemic infiltration into the spleen, liver, and thymus. Mechanistically, transcriptomic profiling of Setd5-deficient CD3+ T-ALL cells reveals selective repression of transcriptional programs governing cell migration, motility, and cytoskeletal organization. Key regulators of actin cytoskeleton remodeling and extracellular matrix interaction-including Plxnb2, Mmp14, Ceacam1, and Clstn1-are among the most downregulated genes, as validated by RT-qPCR. Furthermore, SETD5 knockdown in human T-ALL cell lines Jurkat and MOLT-4 cells result in a marked reduction in proliferation and migration. Our findings demonstrate that SETD5 contributes to T-ALL progression by regulating transcriptional programs that contribute to leukemic cell migration and infiltration, suggesting that SETD5-associated transcriptional programs warrant further investigation as potential vulnerabilities in T-ALL.

KLF4/MLL3 complex axis drives NRBP2 transcription to eliminate acute myeloid leukemia cells.

Epigenetic Reactivation of Lineage Differentiation to Target Leukemia

CD59 organizes the plasma membrane to sustain oncogenic Ras-MAPK signaling and is a targetable vulnerability in acute myeloid leukemia

Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia.

Acute myeloid leukemia (AML) persistence and relapse are sustained by leukemia-propagating cells, yet the molecular programs supporting their expansion during disease evolution remain incompletely understood. Using serial patient-derived xenotransplantation, we establish a longitudinal model in which leukemia-initiating capacity progressively increases. Integrated single-cell transcriptomics and multi-omics profiling reveal a predominantly non-genetic trajectory that follows a conserved pattern across models and is associated with coordinated changes across epigenetic, transcriptional, and proteomic layers. Ribosome profiling and rRNA 2'-O-methylation analyses further support a stage-specific increase in translational activity with ribosome remodeling in advanced xenografts. A pharmacological screen of 3,247 compounds uncovers a limited set of vulnerabilities that consistently emerge during disease progression, including CRBN-dependent degradation of GSPT1 (CC-885) and IAP antagonism (AZD5582). In vivo validation shows that both agents markedly reduce leukemic burden, impair leukemia propagation, and enhance cytarabine activity in patient-derived xenograft (PDX) models. Together, these findings show that leukemic propagation is driven by a non-genetic remodeling program, providing a framework to prioritize and test stage-specific therapeutic strategies in AML.