Welcome to the February 2026 issue of the monthly Preprint watch, brought to you by the ISEH Publication Committee. This month, we deep dive into the most recent preprints focusing on Acute Myeloid Leukemia, a subject of intense activity for both fundamental and translational research. And as usual, if you would like to see your work featured here, you can fill out this form and be featured in the March issue!

 

Dynamics of Ribosomal RNA Transcription and Abundance in Normal and Leukemic Hematopoiesis

https://www.biorxiv.org/content/10.1101/2025.08.01.668217v1

A new single-cell survey of ribosomal RNA production during mouse blood formation challenges the notion that rRNA transcription is a purely housekeeping process. The study finds that rRNA abundance varies strongly by cell type and does not track with cell cycling or protein output. Myeloid cells—especially leukemic progenitors in AML—carry strikingly elevated levels of both nascent and mature rRNAs. The resulting atlas suggests that altered ribosome biogenesis may be a defining molecular feature of leukemic transformation.

 

Multiscale RNA editing analysis reveals cell type specific regulatory programs across disease states in acute myeloid leukemia

https://www.biorxiv.org/content/10.64898/2026.02.04.703797v1

A multiscale single-cell analysis maps the landscape of A-to-I RNA editing in AML across diagnosis, remission, and persistent disease. The study uncovers nearly 3,000 recurrent editing sites, many enriched in immune-related regions, with striking cell type– and condition-specific patterns. Leukemia-associated cell states show reduced editing compared to healthy counterparts, while T cells carry consistent editing shifts across disease stages. The findings position RNA editing as a dynamic, lineage-restricted regulatory layer with potential biomarker relevance in AML.

 

FTO depletion does not alter m6A stoichiometry in AML mRNA: a reassessment using direct RNA nanopore sequencing

https://www.biorxiv.org/content/10.1101/2025.10.22.681652v1

A study using quantitative nanopore RNA sequencing challenges the prevailing view that the RNA demethylase FTO drives AML by erasing m6A marks from oncogenic transcripts such as MYC. Across multiple AML models, m6A levels remained unchanged after genetic or pharmacologic FTO inhibition, while the widely used inhibitor FB23-2 proved cytotoxic even in FTO-deficient cells. Instead, FTO loss increased m6Am modifications in snRNAs, pointing to a different molecular target. The findings call for a reassessment of FTO’s proposed role as an m6A “eraser” in leukemia biology.
 

Single-cell long-read genotyping of transcripts reveals discrete mechanisms of clonal evolution in post-myeloproliferative neoplasm acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.08.18.670417v2

A new long-read single-cell platform, LOTR-Seq, pushes past technical barriers to simultaneously genotype dozens of expressed genes—including low-expression drivers like JAK2—while capturing full transcriptomes. Applied to chronic-phase MPN and post-MPN AML samples, the approach maps how mutations in JAK2, TP53, IDH1/2 and spliceosome genes align with distinct transcriptional states. The data expose the layered genetic architecture underlying progression from MPN to secondary AML. By tightly linking genotype to cell state, LOTR-Seq offers a sharper view of clonal evolution in myeloid disease.

 

Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia

https://www.biorxiv.org/content/10.1101/2025.11.27.690982v1

Proteostasis stress emerges as a key evolutionary pressure shaping aging hematopoietic stem cells, according to a new study that places the stress-response factor HSF1 at the center of clonal selection. While HSF1 activation normally helps aged stem cells maintain protein quality and function, pre-leukemic DNMT3A-mutant cells exploit this pathway to survive inflammatory and proteotoxic stress. In models carrying cooperating DNMT3A and NRAS mutations, disrupting HSF1 or proteostasis slows clonal expansion, delays leukemia onset, and extends survival. The work identifies protein-homeostasis control as a critical bridge between stem-cell aging and leukemic evolution.

 

Methylation dynamics in the decades preceding acute myeloid leukaemia

https://www.biorxiv.org/content/10.1101/2025.06.26.661643v1

A rare longitudinal blood collection tracking individuals up to 15 years before diagnosis reveals that epigenetic disruption in AML begins far earlier than previously recognized. Thousands of DNA methylation changes occur up to a decade before disease onset, many of which are linked to expanding clones carrying known driver mutations. The study also distinguishes early “epigenetic driver” regions from widespread passenger methylation marks that trace clonal growth. Together, the findings suggest that long-term methylation monitoring could enable early detection and refined risk prediction for AML.
 

A Rapid Gene Expression Profiler Classifies AML Tumor Responsiveness to Standard Therapies

https://www.biorxiv.org/content/10.1101/2025.10.08.681215v1

A new rapid qPCR-based diagnostic platform aims to bring real-time gene-expression profiling into frontline AML treatment decisions. By measuring cell-state, stemness, and BCL2-family signatures, the test predicts patient responses to intensive chemotherapy versus hypomethylating agent–venetoclax therapy. In validation cohorts, promonocyte-like transcriptional signals and BCL2 expression significantly improved response and survival prediction beyond genetic markers alone. The approach could enable faster, more precise therapy stratification at diagnosis.
 

Prognostic and Therapeutic Implications of BRAF Mutations in Acute Myeloid Leukemia

https://www.biorxiv.org/content/10.1101/2025.10.14.682328v1

From the authors: Canonical and non-canonical BRAF mutations are enriched in AML-MR and associate with poor survival outcomes. Single-cell multiomic profiling revealed unique co-mutation patterns and immunophenotypes that highlight RAS pathway addiction and nominate BRAF-mutated disease as a distinct subtype within RAS pathway-aberrated leukemias. Drug sensitivity screens suggest broad CDK or HSP90 inhibition in addition to BRAF/RAS-directed inhibition may be effective targeted therapies in this prognostically poor AML subtype.
 

Epigenetic silencing of transposable elements by IRF2BP2 is a selective dependency of myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.11.12.688028v1

A single-cell Perturb-seq screen in primary AML samples identifies the transcriptional repressor IRF2BP2 as an unexpected leukemia dependency. Disabling IRF2BP2 unleashes transposable element expression—especially HERV-K—driving leukemic cells toward differentiation and apoptosis. The study shows that IRF2BP2 partners with TRIM28 and DNMT1 to keep these elements epigenetically silenced, and that forced HERV-K activation alone can reproduce the anti-leukemic effects. The results highlight transposable elements as latent tumor-suppressive circuits that could be therapeutically reactivated in AML.

 

Mutant ASXL1 Drives Transcriptional Activation and Repression in Human Hematopoiesis

https://doi.org/10.64898/2026.01.13.699315

A CRISPR-engineered human stem-cell model sheds new light on how ASXL1 mutations fuel AML. Truncating mutations stabilize the mutant protein, suppress stress-response programs, and boost clonogenicity and engraftment capacity. Mechanistically, mutant ASXL1 rewires transcription through BRD4-dependent pause release while repressing gene expression via a newly identified interaction with MECOM. The work reveals previously unrecognized transcriptional dependencies that could be exploited therapeutically in ASXL1-mutant AML.

 

ASXL1 truncating mutations drive leukemic resistance to T cell attack

https://www.biorxiv.org/content/10.1101/2025.05.29.656798v2 

ASXL1 mutations could be a genetic driver of resistance to donor lymphocyte infusions (DLI) in post-transplant leukemic relapse. Single-cell transcriptomics revealed that ASXL1-mutant AML exhibits a leukemic stem cell–like state with HLA-I suppression. CRISPR correction of ASXL1 restored HLA-I via increased H3K4Me3 deposition and enhanced CD8⁺ T cell recognition and killing. EZH2 inhibition bypassed ASXL1mut-mediated HLA-I suppression, reactivating T cell cytotoxicity. These findings suggest EZH2 inhibition as a strategy to overcome DLI resistance in ASXL1-mutant AML.

 

Direct Binding of miR-155 to FLT3 Regulates Key Cellular Functions in Acute Myeloid Leukemia

https://www.biorxiv.org/content/10.64898/2026.01.15.696285v1

New research links the microRNA miR-155 to the survival advantage of FLT3-ITD–mutant AML cells. Loss-of-function experiments show that inhibiting miR-155 triggers apoptosis and curbs proliferation by directly targeting FLT3. The findings suggest that miR-155 is a key regulator of FLT3-driven leukemogenesis and could serve as a therapeutic target in this high-risk AML subset.
 

Structure-Guided Discovery and Characterization of Novel FLT3 Inhibitors for Acute Myeloid Leukemia Treatment

https://www.biorxiv.org/content/10.1101/2025.06.26.661886v1

Using a structure-based in silico pipeline, researchers have identified two new candidate FLT3 inhibitors with strong predicted binding to the kinase domain. Virtual screening, docking, and molecular dynamics simulations suggest stable target engagement and favorable drug-like properties. The work illustrates how integrated computational strategies can accelerate the search for next-generation FLT3 inhibitors in AML.

 

PSP-0119: Targeted IRAK4 Degradation as a Novel Therapeutic Strategy for FLT3-Mutant AML

https://www.biorxiv.org/content/10.1101/2025.09.30.679569v1

A novel PROTAC degrader targeting IRAK4 shows selective anti-leukemic activity in FLT3-mutant AML models. The compound PSP-0119 induces IRAK4 degradation, suppresses NF-κB signaling, and reduces leukemia cell viability and xenograft growth while sparing normal marrow cells. Transcriptomic analyses further reveal downregulation of poor-prognosis pathways, and the agent demonstrates synergy with IRAK1 inhibition.

 

Organelle proteomics reveals novel metabolic vulnerabilities in FLT3-ITD cells

https://www.biorxiv.org/content/10.64898/2026.01.19.700272v1

A proteomics-driven study reveals that the FLT3-ITD insertion site shapes subcellular protein organization, autophagy, and mitochondrial metabolism, dictating tyrosine kinase inhibitor sensitivity in AML. FLT3-ITD cells with TKI-resistant insertion sites show altered organelle dynamics and metabolic states, but restricting lipids enhances FLT3 trafficking to the plasma membrane and restores midostaurin sensitivity. This work highlights lipid-dependent control of FLT3 compartmentalization as a novel strategy to overcome TKI resistance in AML.
 

Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors

https://www.biorxiv.org/content/10.1101/2025.11.21.689510v1

FLT3 inhibitor resistance in FLT3-ITD AML is often driven by NRAS mutations, which upregulate plasma-membrane–localized SPHK1. Targeting S1P signaling with S1PR modulators, including fingolimod and mocravimod, resensitizes NRAS-mutated FLT3-ITD AML cell lines and patient blasts to FLT3 inhibitors. In vivo, fingolimod restores gilteritinib sensitivity in NRAS-mutated AML. Mechanistically, co-treatment inactivates ERK, AKT, p70S6K, and BAD, and downregulates SPHK1, with effects reversed by constitutive SPHK1. 

 

PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade

https://www.biorxiv.org/content/10.64898/2026.01.20.700677v1

This study defines “stem-monocytic AML,” a leukemia subtype co-expressing HSC- and monocytic-like transcriptional programs that confers venetoclax resistance despite HSC features. Single-cell analyses reveal that differentiated monocytic populations survive BCL2 inhibition, driven in part by PU.1–mediated myeloid transcription. Targeting PU.1 genetically or pharmacologically restores venetoclax sensitivity, highlighting a combinatorial PU.1 and BCL2 inhibition strategy.
 

Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response

https://www.biorxiv.org/content/10.1101/2025.06.06.657881v1

AML cells resistant to venetoclax exploit acid ceramidase (AC) to neutralize tumor-suppressive ceramide. Co-targeting AC with the inhibitor SACLAC restores venetoclax sensitivity, triggering ceramide-driven integrated stress responses, NOXA upregulation, mitochondrial dysfunction, and caspase-dependent cell death. This strategy matches the efficacy of standard venetoclax and cytarabine therapy ex vivo, highlighting AC inhibition as a promising approach to overcome venetoclax resistance in AML.

 

Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 and BCL2 Inhibitors in Acute Myeloid Leukemia

https://www.biorxiv.org/content/10.1101/2025.06.10.658786v1

In AML, activated RAS drives resistance to FLT3 inhibitors and venetoclax, creating a major therapeutic hurdle. The RAS(ON) inhibitor RMC-7977 potently kills AML cells with MAPK-activating mutations, restores FLT3i and venetoclax sensitivity in resistant models, and reduces leukemia burden in RAS-mutant PDX mice. These results position broad-spectrum RAS(ON) inhibition as a strategy to overcome therapy resistance.

 

Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate

https://www.biorxiv.org/content/10.1101/2025.10.27.684888v2

This study demonstrates that pitavastatin, an HMG-CoA reductase inhibitor, can overcome venetoclax resistance in AML by inducing apoptosis through p53-independent upregulation of PUMA and downregulation of MCL-1. Pitavastatin also suppresses mitochondrial gene expression and oxidative metabolism, targeting metabolic pathways that contribute to venetoclax resistance. 

 

Romaciclib, a CDK8/CDK19 inhibitor, can overcome venetoclax resistance through a combinatorial strategy

https://www.biorxiv.org/content/10.64898/2025.12.16.693978v2

Romaciclib (RVU120), a CDK8/CDK19 inhibitor, synergized with venetoclax (VEN) in AML cell lines and patient-derived samples, including models with stroma-mediated or transcriptionally driven VEN resistance. Mechanistically, the combination induced caspase-dependent MCL-1 cleavage and suppressed IL6/JAK/STAT3, TGF-β, PI3K/AKT/mTOR, and inflammatory pathways. In vivo, RVU120+VEN reduced leukemia burden, decreased leukemia-initiating cells, and restored bone marrow function in VEN-resistant PDX models.
 

H1.3 depletion in AML cells prompts H1.2 redistribution, chromatin remodeling and cell cycle defects

https://www.biorxiv.org/content/10.1101/2025.07.28.667197v1

This study uncovers a locus-specific role for the linker histone H1.3 in AML cells. H1.3 preferentially occupies GC-rich, H3K27me3-marked regions, enforcing chromatin compaction and gene repression. Loss of H1.3 triggers H1.2 redistribution, alters chromatin landscapes, and activates interferon signaling while disturbing cell-cycle regulation. The findings highlight how H1 variant imbalance can reshape epigenetic control, linking chromatin architecture to immune and proliferative pathways in leukemia.

 

CCAAT-enhancer binding protein delta functions as a tumor suppressor gene in acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.08.25.670309v1

New evidence positions CEBPD as a tumor suppressor in AML. Knockdown of CEBPD accelerates cell growth and activates MAPK signaling, while its upregulation promotes myeloid differentiation via CD14 expression. The study also implicates DNA methylation in silencing CEBPD during leukemogenesis, reinforcing its role as a critical brake on AML progression.

 

Diverse epigenomic mechanisms underpin transcriptional dysregulation in Polycomb-altered acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.08.28.672871v1

Partial loss of PRC2 function in AML reshapes chromatin and transcription. Heterozygous EZH2 deletion boosts genome-wide accessibility and alters histone marks, yet largely preserves 3D chromatin architecture. These epigenetic shifts activate fetal hematopoiesis programs, including LIN28B and CDK6, linking PRC2 depletion to slower proliferation and resistance to CDK6 inhibition. The study highlights how nuanced changes in chromatin regulation can drive AML aggressiveness and therapy response.
 

siRNA Mediated Genetic Perturbation of Primary Human Leukemia Stem and Progenitor Cells

https://www.biorxiv.org/content/10.1101/2025.09.17.676969v1

A new method overcomes a longstanding hurdle in leukemia research by enabling efficient siRNA-mediated gene knockdown in primary leukemia stem and progenitor cells (LSPCs). Electroporation delivers RNA into the nucleus without harming cell viability, producing robust target suppression with biologically meaningful effects. This advance opens the door to functional studies of LSPCs from patient samples, offering a path to uncover new therapeutic targets in AML and MDS.

 

Integration of an anellovirus genome in the SKNO-1 acute myeloid leukemia cell line

https://www.biorxiv.org/content/10.64898/2026.01.22.701047v1

From the authors: Anelloviruses are a curious group of highly genetically diverse single-stranded DNA viruses that have been found ubiquitously among humans and are hypothesized to be a potential commensal human virus. Their omnipresence has been matched only by the dearth of our understanding of their basic biological processes – how they persist, how they replicate, and how they spread. Here we identify a naturally integrated Alphatorquevirus genome in the widely used AML cell line SKNO-1 and show that it is stably maintained, transcribed, and embedded within a rDNA locus on human chromosome 21. This discovery highlights the ability to anelloviruses to integrate into human DNA, generates hypotheses around transcription factors used in anellovirus gene transcription, and suggests anelloviruses can persist in myeloblasts.

 

Cheminformatic identification of small molecules targeting acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.05.20.655224v1

A structure-blind screen of 4.2 million compounds has surfaced a new class of AML-selective agents that strike mitochondrial function on multiple fronts. These molecules combine apoptotic activation, glutathione reductase inhibition, and autophagy induction—driving ROS accumulation, metabolic collapse, and leukemia cell death. Biophysical assays point to glutathione reductase as a direct target, while distinct chemical scaffolds reproduce the same phenotype. Notably, the compounds synergize with midostaurin, highlighting a promising combination strategy for AML therapy.

 

Mitochondrial Integrated Stress Response Activation Creates a Therapeutic Vulnerability to MCL-1 Inhibition in Acute Myeloid Leukemia

https://www.biorxiv.org/content/10.64898/2025.12.01.691686v1

Researchers show that blocking electron transport chain complex I creates a synthetic lethal interaction with MCL-1 inhibition, reducing leukemia viability and extending survival in patient-derived xenograft models. Mechanistically, complex I suppression activates a DELE1–HRI–ATF4 stress pathway that sensitizes cells to apoptosis. The findings provide a strong preclinical rationale for dual metabolic–apoptotic targeting in high-risk AML, including KMT2A-rearranged disease.

 

TOE1 influences canonical Wnt signalling in myeloid leukaemia cells through LEF-1 modulation and regulates the proliferation of haematopoietic cells through PAK2.

https://www.biorxiv.org/content/10.64898/2025.12.11.691106v1

A newly identified partner of β-catenin, the deadenylase TOE1, emerges as a previously unrecognized regulator of Wnt signaling in AML. TOE1 is overexpressed in leukemia blasts, supports Wnt transcriptional activity, and promotes cell proliferation and survival, partly through maintaining LEF-1 and PAK2 expression. Depleting TOE1 disrupts these pathways and suppresses leukemic growth in cell lines and primary cells. The findings point to the β-catenin–TOE1 axis as a potential vulnerability in Wnt-dependent AML.
 

PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML

https://www.biorxiv.org/content/10.1101/2025.08.17.670714v1

From the authors: Pyrrolobenzodiazepine(PBD)-conjugated anti-CCRL2 ADC shows anti-leukemic effect in MDS/AML models including TP53-mutated disease without affecting healthy hematopoietic cells supporting that it is a promising candidate for single-agent or combination therapies in high-risk MDS/AML.

 

TP53-mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition

https://www.biorxiv.org/content/10.1101/2025.10.01.679539v1

A large genomic analysis identifies a previously underrecognized subtype of TP53-mutated AML marked by recurrent chromosome 3p deletions that remove ribosomal protein genes. Combined losses on 3p and 5q drive a ribosomopathy-like state with suppressed protein synthesis, suggesting cooperative translational defects in leukemogenesis. Drug screening reveals heightened sensitivity of these cases to HSP90 inhibition, pointing to ribosomal stress as a potential therapeutic vulnerability.

 

Targetable BIRC5 dependency in therapy-resistant TP53-mutated acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.05.17.654633v2

From the authors: BIRC5 upregulation is a novel dependency in TP53-mutant AML that mediates therapy resistance by evasion of apoptosis. Combination with Survivin/IAP inhibitors overcomes venetoclax/azacitidine resistance in TP53-mutant AML.

 

TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade

https://www.biorxiv.org/content/10.1101/2025.08.28.672283v1

In TP53-mutant AML, resistance to venetoclax plus azacitidine (VenAza) arises not from impaired mitochondrial priming but from a blockade of apoptosis downstream of mitochondrial outer membrane permeabilization (MOMP). Despite intact MOMP and BIM-mediated pro-apoptotic signaling, these cells fail to activate caspase-3/7, creating a “post-MOMP brake” that decouples mitochondrial permeabilization from cell death. This identifies the terminal execution phase of apoptosis as a critical vulnerability and a potential therapeutic target to overcome VenAza resistance in TP53-mutant AML.

 

Integrating Human Genetics and Protective Genome Editing to Enable ADGRE2-Directed AML Therapy

https://www.biorxiv.org/content/10.1101/2025.08.21.671614v1

This study proposes a “shielded immunotherapy” strategy to safely target ADGRE2, a broadly expressed AML antigen that also appears on normal hematopoietic cells. CRISPR and base-editing approaches achieved efficient ADGRE2 knockout in healthy stem cells without impairing engraftment or differentiation, suggesting they could be transplanted as protected grafts. In parallel, newly engineered ADGRE2-directed CAR-T cells showed potent killing of AML cells even at low antigen levels. The combined approach outlines a path toward effective AML immunotherapy while minimizing on-target myelotoxicity.

 

Effective imaging and treatment of Acute Myeloid Leukemia with radiotheranostics targeting the activated conformation of integrin-βeta2

https://www.biorxiv.org/content/10.1101/2025.08.21.671206v1

From the authors: This study demonstrates promising preclinical efficacy of aITGB2-targeted radiotheranostics for selective imaging and therapy in AML.

 

A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.04.29.651188v1

A structure-based signaling model has uncovered unexpected drug combinations capable of shutting down RAS–ERK signaling in RAS-mutant AML. Pairing distinct conformational classes of RAF inhibitors produced strong synergy in cell lines, patient samples, and xenograft models, significantly delaying leukemia progression compared with single agents. The results demonstrate how computational pathway modeling can identify non-obvious combination therapies for otherwise difficult-to-target oncogenic pathways.
 

5-azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia

https://www.biorxiv.org/content/10.1101/2025.06.24.661348v1

From the authors: RNA-dependent effects of 5-azaC are sufficient to drive leukemia cell cytotoxicity through transcriptional repression. 5-azaC-induced caRNA m5C depletion impairs MBD6 binding and H2AK119ub deubiquitination. 5-azaC-induced caRNA m5C depletion disrupts SRSF2 chromatin-binding, impeding p300 recruitment and H3K27ac deposition. TET2 or IKZF1 depletion synergizes leukemia sensitivity to 5-azaC

 

Dual Targeting of IKKβ and NR4A1 for AML Therapy

https://www.biorxiv.org/content/10.1101/2025.09.24.678355v1

From the authors: IKKβ and NR4A1 are clinically relevant mediators of AML pathogenesis. A novel celastrol-based PROTAC can effectively degrade both IKKβ and NR4A1 to disrupt AML pathogenesis.

 

Sensitivity to ATR-CHK1 pathway inhibition in AML/MDS is enhanced by SRSF2 mutations and reduced by RUNX1 loss

https://www.biorxiv.org/content/10.1101/2025.10.06.680457v1

Patient samples and engineered models reveal that SRSF2 and U2AF1 mutations sensitize leukemia cells to ATR–CHK1–WEE1 pathway inhibitors, identifying these alterations as predictive biomarkers of response. However, concurrent RUNX1 mutations confer resistance, highlighting a key genomic modifier of therapeutic efficacy. The findings suggest that integrating splicing and transcription factor mutation status could refine patient stratification for DNA damage–response–targeted therapies.
 

Balancing Activation and Repression: CoREST-p300 Antagonism Controls Retinoic Acid-Driven Differentiation in AML

https://www.biorxiv.org/content/10.1101/2025.10.13.682235v1

From the authors: Co-inhibition of LSD1 and HDACs with Corin, combined with ATRA, reprograms chromatin by replacing CoREST with p300, uniquely activating differentiation-associated genes and offering a targeted strategy for treating AML. 

 

IGF2BP3 remodels the microRNA targeting landscape in MLL-AF4 leukemia

https://www.biorxiv.org/content/10.1101/2025.10.10.681741v1

A new study uncovers how the RNA-binding protein IGF2BP3 (I3) fuels MLL-AF4 leukemia: by shielding key mRNAs from RISC-mediated repression. Loss of I3 enhances miRNA targeting, particularly by miR-181a, reducing oncogenic transcript expression and mimicking I3 depletion. Biochemical assays confirm that I3 directly competes with AGO2–miRNA complexes at 3′UTRs, revealing a post-transcriptional mechanism by which I3 amplifies leukemic gene programs.

 

Menin maintains enhancer-promoter interactions in a leukemia-specific manner

https://www.biorxiv.org/content/10.64898/2026.01.16.698179v1

Menin, a key cofactor in MLL-rearranged and NPM1-mutant AML, shows strikingly different transcriptional roles depending on leukemia context. In MLL-AF4 cells, Menin maintains enhancer-promoter contacts and regulates widespread transcription, whereas in NPM1c cells, its direct targets are few. Proteomic analyses reveal that Menin engages distinct protein complexes in each setting, explaining these context-dependent effects. The study clarifies why Menin inhibitors elicit variable responses and highlights the importance of protein complex composition in therapeutic sensitivity.

 

Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML

https://www.biorxiv.org/content/10.1101/2025.10.13.681683v1

A high-throughput screen reveals that combining menin and LSD1 inhibition produces striking synergy against MLL-rearranged AML. LSD1 cooperates with the menin-MLL-LEDGF complex to maintain leukemogenic chromatin at H3K36me3-marked loci, and dual inhibition dismantles this axis, repressing HOXA9, MYC, and FLT3 while promoting myeloid differentiation. In xenograft models, the combination markedly reduces leukemia burden and extends survival.

 

Combinatorial inhibition of LSD1 and Menin induces therapeutic differentiation in AML

https://www.biorxiv.org/content/10.1101/2025.11.09.687496v1

From the authors: Inhibition of LSD1 and Menin synergizes to induce differentiation of MLL-r and MLL-WT AMLs. Inhibition of Menin downregulates drivers of proliferation and stemness. Inhibition of LSD1 induces differentiation-associated inflammatory and interferon responses. LSD1 and Menin occupy different areas of the genome.

 

Dynamic BH3 profiling predicts clinical outcomes in acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.10.14.682414v1

From the authors: Dynamic BH3 profiling can be performed on bone marrow and leukemic blood from AML patients in 48 hours. Known clinical prognostic factors associate with drug-induced apoptotic priming in AML. Drug-induced apoptotic priming identifies drug vulnerabilities in individual patients and predicts clinical response to chemotherapy and small molecule inhibitors.
 

A Druggable Tumor Suppressor and Leukemic Stem Cell Marker

https://www.biorxiv.org/content/10.1101/2025.10.16.682831v4

A multimodal LLM-driven study identifies AT2R (AGTR2) as a tumor suppressor and marker of leukemic stem cells in AML. AT2R⁻ cells drive relapse, survive chemotherapy, and initiate leukemia in xenografts, whereas AT2R⁺ cells do not. Epigenetic silencing, rather than mutation, underlies AT2R loss. Enforced AT2R expression or pharmacologic activation with the agonist C21 suppresses AML stemness, impairs fatty acid metabolism, inhibits key signaling pathways (GSK3, PI3K/AKT, Wnt/β-catenin), and delays leukemogenesis.
 

CD33 Epitope Editing Unlocks UM171-Expanded Cord Blood Grafts for AML Immunotherapy

https://www.biorxiv.org/content/10.1101/2025.05.07.652621v1

Scientists developed a strategy to protect hematopoietic stem and progenitor cells (HSPCs) from CD33-targeted AML therapies using base editor–mediated epitope engineering. By precisely disrupting the CD33 epitope required for gemtuzumab ozogamicin binding while preserving its normal function, edited cord blood HSPCs maintained multilineage engraftment, T-cell output, and resistance to drug-induced toxicity in xenografts. This approach enables safer integration of CD33-directed immunotherapies without compromising anti-leukemic efficacy.
 

Dual targeting a LIN28B:β-catenin axis in acute myeloid leukaemia

https://www.biorxiv.org/content/10.64898/2026.01.25.698240v1

From the authors: β-Catenin interacts with the let7 regulating RNA-binding protein (RBP) LIN28B in myeloid and lymphoid cell lines, and primary fetal hematopoietic stem cells (HSC). LIN28B regulates LEF-1 expression and subsequent Wnt/β-catenin signalling output, through a novel post-transcriptional mechanism in leukaemia cells. Dual targeting of β-catenin and LIN28B through either genetic or pharmacological means enhances the killing of leukaemia cell lines.

 

Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML

https://www.biorxiv.org/content/10.1101/2025.05.13.651470v1

A subset of AML is revealed to be serine auxotrophic, relying entirely on external serine due to suppression of the enzyme PSAT1. These leukemias are sensitive to dietary serine/glycine (SG) restriction, which can be rescued by restoring PSAT1. SF3B1 mutations heighten dependence on PHGDH, and SG restriction synergizes with venetoclax, while MECOM-rearranged AMLs are strongly linked to PSAT1 suppression. The work identifies a metabolically vulnerable AML subtype amenable to targeted nutritional and therapeutic interventions.

 

Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.06.26.661633v1

AML exhibits a surprising dependency on riboflavin, not just for energy production but also for nucleotide biosynthesis and iron-sulfur cluster function. Limiting riboflavin or disrupting its metabolism triggers DNA damage, destabilizes Fe-S proteins, and impairs leukemia cell survival. Notably, riboflavin restriction synergizes with BCL-2 inhibition, revealing a metabolic vulnerability that could be exploited therapeutically in AML.

 

The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy

https://www.biorxiv.org/content/10.1101/2025.07.13.664609v1

Despite being highly expressed in AML, the glutamate/aspartate transporter EAAT1 is dispensable for leukemia growth and chemotherapy response. Inhibition of EAAT1 blocks aspartate uptake but does not limit proliferation or sensitize cells, as AML cells maintain aspartate through alternative pathways. These results suggest that targeting EAAT1 alone is unlikely to provide therapeutic benefit, highlighting the metabolic flexibility of AML in sustaining pyrimidine biosynthesis.

 

MYST acetyltransferases are a targetable therapeutic vulnerability in SETBP1-mutant leukemia

https://doi.org/10.64898/2026.01.08.697228

From the authors: SETBP1 mutations are markers of high-risk myeloid malignancies, but we lack any targeted therapies to improve outcomes. In this study, we identify MYST acetyltransferases as key drivers of mutant SETBP1-driven transcription. MYST inhibitors are highly effective against SETBP1-mutant leukemia and represent a promising avenue for clinical translation.

 

BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia

https://www.biorxiv.org/content/10.64898/2026.01.19.700325v1

From the authors: Aberrant RNA splicing and metabolic reprogramming are hallmarks of cancer, yet how these processes are mechanistically linked remains unclear. This study identifies BCLAF1 as a key regulator connecting splicing control to amino acid metabolism in acute myeloid leukemia, revealing a previously unrecognized functional vulnerability at the intersection of these pathways.

 

Targeting USP2 induces degradation of PML-RARα with or without drug-resistant mutations in acute promyelocytic leukemia

https://www.biorxiv.org/content/10.1101/2025.05.11.653221v1

Researchers report a new vulnerability in acute promyelocytic leukemia (APL) resistant to standard ATRA/ATO therapy: the deubiquitinase USP2. Blocking USP2 destabilizes the oncogenic PML-RARα fusion protein—even in drug-resistant mutants—by restoring its proteasomal degradation. The inhibitor ML364 triggers substantial apoptosis in leukemia cells and patient samples. The findings point to USP2 inhibition as a potential strategy to overcome treatment resistance in relapsed APL.

 

Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells

https://www.biorxiv.org/content/10.1101/2025.07.11.663968v1

Leukemic stem cells in AML rely on the P110α isoform of PI3K, but PI3K inhibition triggers compensatory changes in EZH2/PRC2, with EZH1 upregulation driving resistance. Combining PI3K inhibitors with dual EZH1/2 blockade overcomes this adaptive resistance, effectively targeting AML cells and LSCs in ex vivo assays and mouse and PDX models. 
 

Inducing TRIB2 Targeted Protein Degradation to Reverse Chemoresistance in Acute Myeloid Leukemia

https://www.biorxiv.org/content/10.1101/2025.10.03.680259v1

This study establishes TRIB2 as a critical oncogenic dependency in AML and a promising therapeutic target. TRIB2 drives chemoresistance and blocks differentiation by promoting ubiquitin-mediated degradation of the transcription factor C/EBPα.

 

Macrophage-secreted Pyrimidine Metabolites Confer Chemotherapy Resistance in Acute Myeloid Leukemia (AML)

https://www.biorxiv.org/content/10.1101/2025.11.01.686055v1

Bone marrow macrophages promote chemoresistance in AML by secreting deoxycytidine (dC), which inhibits leukemia cell deoxycytidine kinase and impairs cytarabine activation. High macrophage SAMHD1 drives dC accumulation, and circulating dC rises post-chemotherapy in patients. Inhibiting SAMHD1 or DHODH restores AraC sensitivity and delays relapse in preclinical models, highlighting macrophage metabolism as a target to overcome therapy resistance.

 

Acute Myeloid Leukemia Relapse after Bromodomain Inhibitor Treatment or Chemotherapy is Characterized by Myc-Ras Transcriptional Remodeling

https://www.biorxiv.org/content/10.1101/2025.11.13.688312v1

BET inhibition with PLX51107 suppresses NRAS-mutant AML growth, and efficacy is enhanced by MEK inhibition with PD0325901. In mouse Nras-mutant AMLs, single-agent PLX51107 shows activity that improves with combination therapy. Relapsed leukemias acquire intrinsic resistance via a primitive transcriptional state, upregulating Myc targets and downregulating Ras programs, a pattern also observed after chemotherapy. These findings highlight transcriptional plasticity in AML and support BET inhibitor evaluation in RAS-mutant, monocytic leukemias.

 

LIMK Inhibition and Metformin Block Mitochondrial Transfer Overcoming Macrophage Driven Therapy Resistance in Acute Myeloid Leukaemia

https://www.biorxiv.org/content/10.64898/2026.02.03.702377v1

Chemoresistance in AML is driven in part by interactions with bone marrow macrophages (Mφs). This study shows that M2-like Mφs protect AML cells from daunorubicin and cytarabine–induced apoptosis via mitochondrial transfer through tunneling nanotube–like structures. Blocking transfer with cytochalasin B, TH-257 (LIMK inhibitor), or metformin reduced protection. Transferred mitochondria enhanced AML metabolic capacity and lowered ROS under chemotherapy stress. Transcript levels of RhoC and cofilin correlated with poorer survival, highlighting mitochondrial transfer and LIMK-Cofilin pathway as potential targets to overcome chemoresistance.
 

Menin-Inhibition Sensitizes Acute Myeloid Leukemia to CLEC12A-Directed CAR Cell Therapy

https://www.biorxiv.org/content/10.64898/2026.02.15.703376v1

Menin inhibitors, approved for KMT2A-rearranged and NPM1-mutated AML, induce robust expression of the myeloid antigen CLEC12A (CLL-1) without affecting T or NK cell function. This epigenetic priming sensitizes AML cells to CLEC12A-directed CAR T cells, which efficiently eliminate leukemia in vitro and in xenograft models. Combination therapy outperforms either approach alone, achieving profound disease control and prolonged survival, highlighting a clinically actionable strategy for enhancing CAR-based immunotherapy in AML.

 

Upregulation of Genetic Markers of Poor Prognosis following Chemotherapy in Acute Myeloid Leukemia Cells

https://www.biorxiv.org/content/10.64898/2026.02.12.705420v1

In HL-60 leukemia cells exposed to sublethal doses of three drugs, surviving cells upregulated genes linked to stemness, EMT, inflammation, drug resistance, and apoptosis evasion—many of which correlate with poor prognosis in AML. These results suggest that while treatment reduces tumor burden, it also enhances the malignancy of residual cells, highlighting a tradeoff between cytotoxicity and induction of more aggressive phenotypes.
 

Targeted Irradiation and STAT3 Inhibition Reprogram the AML Microenvironment and Extend Survival: Toward Translational Immunoradiotherapy

https://www.biorxiv.org/content/10.1101/2025.05.14.653587v1

Targeted marrow irradiation (TMI) enhances the efficacy of the myeloid-directed STAT3 inhibitor CSI-2 in high-burden AML. In mouse models, TMI increased AML and myeloid cell uptake of CSI-2, improving leukemia clearance and survival. Combined TMI/CSI-2 treatment promoted CD8⁺ and CD4⁺ T cell infiltration and established long-term immune memory, protecting against AML rechallenge. These results support TMI/CSI-2 as a promising organ-sparing immunoradiotherapy for relapsed or high-burden AML.
 

Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2

https://www.biorxiv.org/content/10.1101/2025.05.22.655396v1

Venetoclax plus azacitidine (ven/aza) resistance in AML is linked to MCL1-dependent sequestration of the transcriptional repressor IRF2BP2 in leukemic stem cells. This cytoplasmic relocalization de-represses target genes, including ACSL1, a key regulator of fatty acid oxidation (FAO). Inhibition of ACSL1 disrupts FAO and impairs ven/aza-resistant LSCs, revealing a mechanism by which MCL1 promotes metabolic adaptation and therapy resistance in AML.
 

Overcoming treatment resistance mediated by the bone marrow vascular niche in acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.05.22.655592v1

AML relapse is driven by quiescent leukemic stem cells (LSCs) protected by microenvironmental signals. Arteriolar endothelial cells (ECs) transfer miR-126 to LSCs, promoting quiescence, niche retention, and resistance. During disease progression, TNF-α from blasts suppresses EC miR-126, allowing LSC proliferation; after TKI therapy, reduced TNF-α restores miR-126, enabling LSCs to re-enter quiescence and evade treatment. Computational modeling of the bone marrow niche predicts that combining TKIs with miRisten, a miR-126 inhibitor, disrupts this protective feedback and enhances LSC eradication.

 

Epigenetic remodeling via HDAC6 inhibition amplifies anti-tumoral immune responses in myeloid leukemia cells

https://www.biorxiv.org/content/10.1101/2025.05.30.654805v3

HDAC6 drives AML progression in vivo, despite little effect on proliferation in vitro. HDAC6 loss or inhibition upregulates the tumor-suppressor RNase T2 in myeloid but not lymphoid leukemia via increased chromatin accessibility. In immunocompetent models, HDAC6 inhibition enhances CD8⁺ T cell activation and limits leukemia growth. HDAC6 inhibitors also synergize with Cytarabine and Clofarabine in myeloid leukemia, including patient-derived xenografts, but not in lymphoid leukemia or healthy cells. These results identify HDAC6 as a therapeutic target that boosts immune response and chemosensitivity in myeloid leukemia.

 

Pro-inflammatory role of granzyme K producing bystander CD8+ T cells in acute myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.08.12.669682v1

The authors identified a bone marrow–enriched population of functional CD69⁺ CD8⁺ T cells that primarily recognize non-tumor antigens, including EBV and CMV epitopes. These bystander T cells express high Granzyme K, which does not kill leukemia cells but promotes IL-8–mediated inflammation, potentially worsening AML progression. This work highlights a pro-inflammatory, non–tumor-reactive CD8⁺ T cell subset and suggests targeting Granzyme K or these bystander T cells as a complementary therapeutic strategy.
 

Mining single-cell transcriptomic data reveals distinct T-cell population in pediatric B-ALL and AML at diagnosis

https://doi.org/10.64898/2026.01.09.698676

Integrated single-cell RNA-seq of 47,610 bone marrow T cells from pediatric B-ALL (n=89), AML (n=26), and healthy donors (n=9) identified 17 transcriptionally distinct subsets. Comparative analysis revealed T-cell populations distinguishing B-ALL from AML, including proliferative, naïve, progenitor exhausted, and regulatory CD4 subsets. A rare hemoglobin-expressing T-cell subset enriched in B-ALL displayed upregulated heme metabolism and hypoxia-related pathways, with higher abundance correlating with improved outcomes. These findings delineate transcriptional heterogeneity in pediatric leukemia T cells and highlight subsets potentially relevant for immunotherapeutic strategies.

 

In vivo vaccine generation with a topical small molecule cocktail to eradicates AML and PDAC

https://www.biorxiv.org/content/10.1101/2025.10.19.683274v1

A novel in vivo vaccine strategy using a small-molecule cocktail demonstrates high efficacy in mouse AML models. The approach triggers immunogenic cell death, releasing tumor antigens and activating NK and dendritic cells, thereby inducing both innate and adaptive immune responses across blood, lymph nodes, spleen, bone marrow, and tumor microenvironment

 

Transplantation in neonate mouse recipients enhances umbilical cord blood CD34+ cells permissiveness to ETO2::GLIS2-driven transformation

https://doi.org/10.64898/2026.01.12.698953

A new xenograft study suggests that the developmental stage of the host niche strongly shapes pediatric leukemia initiation. Human cord-blood progenitors carrying the ETO2::GLIS2 fusion generated acute megakaryoblastic leukemia (AMKL) far more efficiently in neonatal than adult mice, with higher leukemia-initiating cell frequencies and disease penetrance. Despite similar engraftment levels, the neonatal microenvironment proved markedly more permissive to transformation. The findings highlight developmental niche signals as critical drivers of pediatric AMKL and position neonatal models as more physiologically relevant systems for studying disease initiation.
 

An optimized method to differentiate HL60 cells into neutrophil-like cells

https://doi.org/10.64898/2026.01.06.697988

From the authors: The authors provide an improved method to differentiate HL60 cells into neutrophil-like cells that faithfully recapitulates the morphology and functionality of mature human neutrophils.

 

Functionalist Oncology to Model the Contextuality of Dynamics and Treatment in Acute Myeloid Leukemia

https://www.biorxiv.org/content/10.64898/2025.12.22.695906v1

Functionalist oncology applies edge-weighted digraphs to model the interdependencies of disease factors in AML, enabling mechanistic analysis of key determinants of therapeutic success. This framework accounts for the oligoclonal nature of AML and can be parameterized with patient-specific data to evaluate treatment responses, drug combinations, and chemotherapy scheduling. Using cytarabine as a focal point, the approach explores the potential and risks of SAMHD1 inhibitors as a proof-of-concept. This methodology generates testable hypotheses that may guide optimized, individualized treatment strategies in AML.

 

Biases introduced by Ficoll-based isolation in acute myeloid leukemia sample analyses support the use of hemolysis

https://www.biorxiv.org/content/10.64898/2026.02.11.705243v1

Ficoll-based density gradient isolation alters the cellular composition and molecular readouts of AML samples. Compared with hemolysis, Ficoll enriches lymphocytes and AML blasts while depleting granulocytes, increases T-cell–mediated graft-versus-host effects in NSG mice, and skews RNA-seq analyses, including overestimation of leukemic stem cell gene expression and CD8+ T-cell and monocyte abundance. Mutation detection can also be affected, with clinically relevant variants missed in Ficoll-processed samples. 

 

Blog post contributed by Alessandro Donada, PhD (Bluesky: @alessandrodonada.bsky.social) of the ISEH Publications Committee. 

Please note that the statements made by Simply Blood authors are their own views and not necessarily the views of ISEH. ISEH disclaims any or all liability arising from any author's statements or materials.