After missing the month of November, the preprint watch is back, with a selection of the most recent preprints in hematology! This month we focus our attention on chronic hematological malignancies, and the link between pathology and hematopoiesis.

And last but not least, two preprints submitted by the community! If you want your preprint to be highlighted as well, do not wait further and submit it using this link.

 

From the Simply Blood Community:

A platform of robust patient-derived leukemia models covering subgroups for which no cell lines exist

https://www.biorxiv.org/content/10.1101/2025.09.26.677299v1

We present new robust PDX models of acute myeloid leukemia covering subgroups for which no cell lines exist for use in various ex vivo and in vivo applications. These *PDX models enable serial transplantation, genetic engineering and better representation of primary AML biology than cell lines and are a relevant resource holding great promise to accelerate translational research for the benefit of cancer patients.

Contact address: irmela.jeremias@helmotz-munich.de

Social media handles: @jeremiaslab.bsky.social, @Jeremias_lab (LinkedIn)

 

Single-cell spatial mapping reveals dynamic bone marrow microarchitectural alterations and enhances clinical diagnostics in MDS

https://www.biorxiv.org/content/10.1101/2025.10.02.680138v2

We describe spatial mapping of hematopoietic cells at single cell resolution in a large number of clinical bone marrow trephine biopsy samples from MDS patients. Using AI-guided analytics we show how microarchitectural alterations correlate with underlying genetics and dynamically change along the course of therapy in individual patients.

Contact address: sap9151@med.cornell.edu

 

Haematopoiesis and Disease

Hematopoietic Stem Cells Modulate Tumor Immune-Environment to Target Triple-Negative Breast Cancer via Altering Mitochondrial Bioenergetics

https://www.biorxiv.org/content/10.1101/2025.05.07.652451v2

From the authors: Hematopoietic stem cells exhibited tumor tropism towards triple-negative breast cancer stem cells and HER2+ cancer cells. Upon migration in the tumor milieu, HSCs differentiated into T cells, targeted CSCs, and modulated the upregulation of interleukin-7 and Notch proteins. HSCs-conditioned media (HSCs-CM) inhibited the cell cycle in TNBC-CSCs by downregulating CDK1, disrupting mitochondrial bioenergetics via upregulated Drp1, and inducing CSC apoptosis. Paracrine signaling from HSCs via conditioned media induced metabolic stress and disrupted key metabolic pathways in TNBC-CSCs.
 

Ovarian Cancer Drives TLR5-Dependent Expansion of Myeloid Progenitors Through Systemic Dissemination of Ligands

https://www.biorxiv.org/content/10.1101/2025.06.10.658497v1?rss=1

Here, the researchers present evidence that ovarian tumors disrupt gut barrier integrity, allowing TLR5 ligands to circulate systemically and reach the bone marrow. This chronic signaling expands myeloid progenitors in wild-type but not TLR5-deficient mice, driving increased monocyte accumulation in the tumor microenvironment. Pharmacologic TLR5 blockade reshapes bone marrow progenitor composition and alters tumor-associated myeloid populations. These findings reveal a gut–bone marrow axis through which tumor-induced TLR5 activation promotes myeloid expansion and immunosuppressive infiltration in ovarian cancer.

 

Hematopoietic stem cell conditioned media induces excessive mitochondrial fission via Drp-1 to target colorectal cancer

https://www.biorxiv.org/content/10.1101/2025.09.10.675059v1?rss=1

From the authors: Hematopoietic stem cell-derived conditioned media (HSC-CM) induced excessive mitochondrial fission by upregulating the Drp-1 protein, leading to the upregulation of the apoptosis pathway and cell death. The excessive mitochondrial fission and bioenergetic dysfunction induced by HSCs-CM result in a loss of mitochondrial membrane potential (MMP) and high reactive oxygen species (ROS) production. HSCs-CM severely disrupt mitochondrial bioenergetics in CRC cells, leading to an energy crisis and promoting the PINK-1 mediated mitophagy pathway.
 

Childhood brain tumours instruct cranial haematopoiesis and immunotolerance

https://www.biorxiv.org/content/10.1101/2025.09.25.678472v1?rss=1

The authors reveal that ZFTA-RELA ependymomas engage an unexpected immunoregulatory circuit linking cerebrospinal fluid antigens to skull bone marrow HSPCs. Antigen presentation by these HSPCs to CD4⁺ T cells skews progenitors toward myelopoiesis and polarizes T cells toward a regulatory phenotype, collectively fostering tumour immunotolerance. Similar cytokine signatures were observed across multiple pediatric brain tumours. Targeting these cytokines with a single antibody infusion disrupted this HSPC–T-cell axis and triggered marked tumour regression, highlighting a tractable immunological vulnerability with therapeutic potential across aggressive childhood brain cancers.

 

Clonal Hematopoiesis Mutations Increase Risk of Alzheimer’s Disease with APOE ε3/ε3 Genotype

https://www.biorxiv.org/content/10.1101/2025.05.19.654981v1?rss=1

Here, the researchers report that older adults with Alzheimer’s disease carry a substantially higher burden of clonal hematopoiesis (CHIP) mutations than age-matched controls, driven mainly by low-frequency variants missed by standard sequencing. The effect was specific to individuals with the APOE ε3/ε3 genotype and absent in ε4 carriers, and was independently validated in a large WGS cohort. CHIP mutations in AD also showed stronger signatures of positive selection, suggesting active clonal expansion. Together, these findings indicate that expanded CHIP clones affect more than one-third of AD patients and may contribute to disease risk through an APOE ε4-independent mechanism.

 

Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2-deficient CHIP via XPO1 Inhibition and Atf3 restoration

https://www.biorxiv.org/content/10.1101/2025.06.12.658927v1?rss=1

Researchers report that inhibiting nuclear export with eltanexor markedly reduces atherosclerotic plaque formation in a mouse model of Tet2-mutant clonal hematopoiesis, a condition known to amplify inflammatory macrophage activity. Single-cell CITE-seq revealed that Tet2-mutant macrophages—and even non-hematopoietic aortic wall cells—upregulate diverse proinflammatory mediators, a pattern substantially dampened by eltanexor. The team shows that Tet2 loss disrupts ATF3 binding at key enhancer regions controlling inflammatory genes, and that XPO1 inhibition restores this regulatory function. Altogether, the study clarifies how Tet2 mutations intensify inflammation and points to XPO1 inhibition as a promising therapeutic approach.

 

Aggressive Cholesterol Lowering Normalizes Atherosclerosis Regression in Jak2V617F Clonal Hematopoiesis

https://www.biorxiv.org/content/10.1101/2025.07.23.666334v3

In this work, scientists looked at how the Jak2V617F mutation—common in CHIP and MPN—shapes the ability of atherosclerotic plaques to resolve when cholesterol levels are reduced. Transplanting Jak2VF cells in Ldlr−/− recipients (a model for atherosclerosis progression), the authors found that moderate cholesterol lowering failed to resolve lesions in Jak2VF animals, whereas more aggressive LDL reduction halted plaque progression and improved stability in both groups. Deep profiling revealed that strong LDL lowering suppresses AIM2 inflammasome activity and DNA damage in Jak2VF macrophages, while broadly expanding TREM2⁺, c-Myc–expressing macrophages associated with inflammation resolution. Altogether, the study indicates that intensive LDL reduction can counteract Jak2VF-driven inflammatory pathology and may mitigate cardiovascular risk in individuals with JAK2-mutant CHIP or MPN.

 

IL-18 inhibition enlarges lesions, necrotic cores and thickens fibrous caps in Jak2V617F clonal hematopoiesis-driven atherosclerosis

https://www.biorxiv.org/content/10.1101/2025.06.03.657754v1?rss=1

From the authors: Inflammasome activation produces active IL-1 and IL-18 and worsens atherosclerosis in clonal hematopoiesis (CH). Antibody inhibition of IL-18 increased plaque collagen but also increased early lesion area and late lesions with large necrotic cores in Jak2VF CH mice. There was a reversal of AIM2 inflammasome activation but a switch to apoptosis which, along with reduced efferocytosis, increased necrosis. These events appeared to be coordinated by reduced IFN-γ which increased collagen but also decreased expression of efferocytotic genes.
 

Inference of clonal hematopoiesis using the collective behaviour of DNA methylation states

https://www.biorxiv.org/content/10.1101/2025.11.18.689122v2

The study shows that clonal expansion imprints a characteristic structure on DNA-methylation profiles: at allelically transmitted CpG sites, methylation levels converge toward 0%, 50%, or 100% as expanded clones dominate. Using this predictable behaviour, the authors created COMET, a mutation-agnostic method that infers clonal hematopoiesis burden directly from bulk methylation data. Benchmarking against targeted sequencing confirmed accurate detection across diverse driver mutations. Applying COMET to 15,900 individuals recapitulated known genetic associations and links to smoking and COPD, uncovering a general epigenetic signature of clonal dynamics.
 

Clonal Hematopoiesis Associated with TP53 and DNMT3A Mutations Promotes Tissue Repair in Acute Cardiovascular Diseases

https://www.biorxiv.org/content/10.1101/2025.11.23.690015v2

The study identifies a regenerative role for clonal hematopoiesis, showing that CH can enhance tissue recovery rather than universally drive pathology. In a cohort of 125,966 individuals, DNMT3A- and TP53-associated CH was underrepresented among acute cardiovascular disease cases and correlated with fewer rehospitalizations and improved survival. Competitive bone-marrow transplantation models of Dnmt3a- and Trp53-mutant CH demonstrated accelerated repair after myocardial infarction, hindlimb ischemia, and muscle injury. These findings indicate that specific CH genotypes can promote ischemic tissue repair and may offer a basis for therapeutic regeneration strategies.
 

Curing autoimmune diabetes with islet and hematopoietic cell transplantation after CD117 antibody-based conditioning

https://www.biorxiv.org/content/10.1101/2025.09.05.673576v1?rss=1

This work establishes a chemotherapy-free, non-myeloablative conditioning strategy that enables durable mixed chimerism across MHC barriers in NOD mice. The regimen—combining anti-c-Kit and T-cell depletion with JAK1/2 inhibition and low-dose irradiation—prevents diabetes in prediabetic animals and fully reverses overt disease when paired with islet transplantation, all without chronic immunosuppression or GVHD. Chimeric mice retain immune competence while eliminating autoreactive T-cell responses and tolerating donor-matched islets, demonstrating a path toward safe induction of mixed chimerism for durable correction of autoimmunity.

 

Hypercholesterolaemia promotes epigenetic memory in hematopoietic stem cells that persists after lipid lowering and causes systemic immunometabolic dysfunction mediated by macrophage metabolic reprogramming

https://www.biorxiv.org/content/10.1101/2025.09.15.676283v1?rss=1

Researchers show that high cholesterol imprints a lasting pro-inflammatory program on hematopoietic stem cells that persists even after lipid levels normalize. Macrophages derived from cholesterol-exposed HSC maintain altered metabolism, driven by RUNX1-dependent repression of SCD and reduced MUFA availability, leading to sustained inflammatory activity that MUFA supplementation can partially reverse. These epigenetic and metabolic changes propagate to monocytes, tissue macrophages, and whole-body physiology, increasing adipose inflammation and glucose intolerance in normocholesterolemic hosts, revealing a durable immuno-epigenetic memory.

 

Transcriptional and epigenetic repression of hematopoietic stem cells underlies bone marrow failure after spinal cord injury

https://www.biorxiv.org/content/10.1101/2025.10.05.680535v1?rss=1

From the authors: Spinal Cord Injury (SCI) compromises long-term hematopoiesis, preventing stress-induced transcriptional programs in HSCs. DNA repair genes in HSPCs are epigenetically silenced after SCI. SCI HSCs accumulate ROS and DNA damage, are hypersensitive to genotoxic stress and fail long-term hematopoiesis post-transplant.
 

Haematopoietic loss of KDM6A impairs cardiac recovery in heart failure via epigenetic reprogramming of myeloid cells

https://www.biorxiv.org/content/10.64898/2025.12.01.691512v1

Here, the researchers show that KDM6A-driven clonal haematopoiesis profoundly worsens cardiac recovery after myocardial infarction. Using murine models, multi-omics profiling, and patient-derived datasets, they reveal that loss of KDM6A in haematopoietic cells amplifies systemic and cardiac inflammation through epigenetically reprogrammed CCR2⁺ macrophages and neutrophils with intensified inflammatory and chemotactic activity. Patient samples with KDM6A mutations display similarly heightened pro-inflammatory monocyte signatures, reinforcing clinical relevance. The work uncovers inflammatory crosstalk between mutant monocytes and cardiac cells, establishing KDM6A-mutant CH as a contributor to adverse post-MI outcomes.

 

Lymphoid Chronic Malignancies

Time-series RNA-Seq and data-driven network inference unveil dynamics of cell activation, survival and crosstalk in Chronic Lymphocytic Leukaemia in vitro models

https://www.biorxiv.org/content/10.1101/2025.04.20.649300v1?rss=1

In this work, scientists looked at how CLL cells adapt to immune cues by combining time-series transcriptomics with gene regulatory network inference in a reconstructed tumour microenvironment. Across five time points in patient-derived cultures, they uncovered temporally shifting, patient-specific regulatory programs shaped by immune-driven cytokine, metabolic, and differentiation signals. The analyses showed that immune cells strongly modulate CLL activation states, yet intrinsic regulatory features mainly dictate long-term survival trajectories. This framework provides mechanistic insight into immune–CLL interactions while enabling dynamical modelling of CLL cell behaviour.
 

Asymmetric induction of IL-23R by CpG and IL-15 in proliferative CLL fractions highlights intraclonal heterogeneity in chronic lymphocytic leukemia

https://www.biorxiv.org/content/10.1101/2025.08.27.672649v1?rss=1

Here, the authors show that stimulation with CpG oligodeoxynucleotides and IL-15 selectively induces IL-23R and IL-12Rβ1 expression in CLL cells, resulting in robust assembly of the IL-23 receptor complex. This skewing favors pro-inflammatory and pro-survival IL-23 signaling over tumor-suppressive IL-12 pathways. Notably, IL-23R expression is enriched in the proliferative CXCR4^low/CD5^high CLL subfraction, indicating that IL-23 responsiveness is linked to recently divided leukemic cells. 

 

Continuous DNA Methylation Deconvolution-Based Surrogate for B-Cell Differentiation State in CLL

https://www.biorxiv.org/content/10.1101/2025.09.16.676535v1?rss=1

In this study, the authors used genome-wide DNA methylation profiling of purified CLL samples to define a continuous epigenetic differentiation metric, termed the B-Index, spanning B-naive–like to B-memory–like states. The B-Index accurately classified IGHV-mutated and unmutated CLL with high precision and revealed additional epigenetic heterogeneity within M-CLL beyond IGHV status alone. 

 

Reduced CSF1R expression in myeloid cells has limited impact on chronic lymphocytic leukemia progression

https://www.biorxiv.org/content/10.1101/2025.10.07.680920v1?rss=1

From the authors: In summary, our results show that while the CSF1R pathway is important for maintaining the myeloid cells that support CLL, simply reducing CSF1R expression has only a limited effect on disease progression. Attempts to target the CSF1R for leukemic therapy might benefit from a stronger depletion of macrophages or the combination with other agents.

 

Exploring Resistance to ETS Targeting Agents in Diffuse Large B-Cell Lymphoma

https://www.biorxiv.org/content/10.1101/2025.09.18.675797v1?rss=1

In this study, authors investigated mechanisms of resistance to the ETS inhibitor TK216 in Activated B-cell-Diffuse Large B-Cell Lymphoma (ABC-DLBCL). Resistant U2932 clones showed 4–5-fold higher IC50s and lost G2–M arrest. Drug screening revealed retained sensitivity to BCL2, MCL1, and XPO1 inhibitors, whereas aurora kinase and microtubule-targeting drugs were less effective.

 

Enhanced efficacy of a specific HDAC3 inhibitor in combination with 5-Azacitidine against diffuse large B-cell lymphoma

https://www.biorxiv.org/content/10.1101/2025.04.21.648509v1?rss=1

DLBCL tumors exhibit epigenetic dysregulation that blocks germinal center (GC) B-cell exit and plasma cell differentiation, mediated by BCL6 repression via DNA hypermethylation and H3K27 deacetylation through HDAC3. A combinatorial epigenetic therapy using 5-Azacitidine (HMA) and a specific HDAC3 inhibitor (HDAC3i) synergistically reactivates plasma cell differentiation programs, including XBP1 and ATF4, leading to potent anti-tumor effects without affecting normal cells. 

 

Targeting of ibrutinib resistance–driving pathways by miR-28 in ABC-DLBCL

https://www.biorxiv.org/content/10.1101/2025.11.12.687947v1?rss=1

In this study, authors show that microRNA-28 (miR-28) can prevent the emergence of ibrutinib-resistant ABC-DLBCL cells. Using clonal tracking, transcriptomic analyses, and xenograft models, they demonstrate that miR-28 disrupts clonal selection and represses mitochondrial and mTOR signaling pathways critical for resistance. Patient data from the PHOENIX trial further support that lower expression of miR-28 target genes correlates with improved survival in ibrutinib-treated individuals. 
 

AEBP2-Directed H3K27me2 Defines a Specific Vulnerability in EZH2-mutant Lymphoma

https://www.biorxiv.org/content/10.1101/2025.10.14.682307v1?rss=1

Here researchers show that the PRC2 accessory protein AEBP2 is a specific dependency in EZH2-mutant DLBCL. AEBP2 functions within the PRC2 complex to maintain intergenic H3K27me2 independently of canonical H3K27me3-mediated gene silencing. Loss of AEBP2 or NSD2 altered intergenic H3K27me2 levels, affecting sensitivity to PRC2 inhibitors. 
 

Integrating Single-Cell Biophysical and Transcriptomic Features to Resolve Functional Heterogeneity in Mantle Cell Lymphoma

https://www.biorxiv.org/content/10.1101/2025.05.20.655210v1?rss=1

Buoyant mass and stiffness of primary mantle cell lymphoma (MCL) cells correlate with B-cell developmental states and oncogenic B-cell receptor signaling (e.g., BLK, CD79A). Changes in buoyant mass ex vivo predict sensitivity to Bruton’s Tyrosine Kinase inhibitors in MCL and chronic lymphocytic leukemia. These results establish single-cell biophysical properties as complementary biomarkers for functional phenotypes and therapeutic response.

 

Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

https://www.biorxiv.org/content/10.1101/2025.06.25.661613v1?rss=1

This study delineates distinct genetic, transcriptional, and immune landscapes in mantle cell lymphoma with clear prognostic relevance. TP53 alterations defined a high-risk group with proliferative and immunosuppressive features, while ATM mutations were associated with improved outcomes after rituximab-based therapy. Integrated genomic, transcriptomic, and spatial proteomic analyses revealed subtype-specific tumor–immune interactions and identified p53-mediated repression of BCR signaling as a key vulnerability in TP53-altered disease.
 

DC-SIGN Binding to the Surface Ig Oligomannose-type Glycans Promotes Follicular Lymphoma Cell Adhesion and Survival

https://www.biorxiv.org/content/10.1101/2025.07.11.664379v1?rss=1

From the authors: DC-SIGN promotes FL cell adhesion to VCAM-1 via B-cell receptor proximal kinases and actin regulators. DC-SIGN interaction with sIg-Mann sustains the survival of FL cells.
 

Dual targeting of BTK and BCL2 enhances apoptosis in marginal zone lymphoma models: preclinical activity of BGB-16673 and sonrotoclax

https://www.biorxiv.org/content/10.1101/2025.11.24.690186v1?rss=1

Here researchers show that the novel BTK degrader BGB-16673 exhibits single-agent activity in marginal zone lymphoma (MZL) cell lines by degrading BTK and repressing BCR signaling and MYC target genes. Its effects partially overlap with zanubrutinib but also modulate oxidative phosphorylation genes. Combination studies revealed strong synergy with multiple targeted agents, particularly the second-generation BCL2 inhibitor sonrotoclax, enhancing apoptosis and outperforming venetoclax in most models.
 

ARID1A and ARID1B safeguard B cell identity, prevent myeloid transformation and expose therapeutic vulnerabilities in lymphoma

https://www.biorxiv.org/content/10.1101/2025.09.16.676393v1?rss=1

Here researchers examine ARID1A and ARID1B roles in early B cell development. Loss of either gene partially impairs B cell differentiation and germinal center formation, while combined deletion further reduces peripheral B cells, shortens survival, and unexpectedly induces aggressive myeloid leukemia from CD19⁺ multipotent progenitors (MPPs). Deficient MPPs show abnormal expansion, reduced colony formation, and dysregulated stemness and lineage programs.

 

Characterization of lymphoma models for the surface ROR1 expression

https://www.biorxiv.org/content/10.1101/2025.11.19.684505v1?rss=1

From the authors: Here, we characterized a vast panel of lymphoma cell lines for their ROR1 RNA level and ROR1 cell surface protein expression, and showed, using zilovertamab vedotin as proof-of-principle, that these models can be exploited to study this promising class of anti-cancer agents.
 

Whole genome CRISPR knockout screen reveals ID3 as a key regulator of myeloma cell survival via TCF3 and c-MYC

https://www.biorxiv.org/content/10.1101/2025.09.09.675036v1?rss=1

Here, the authors performed a genome-wide CRISPR/Cas9 knockout screen in myeloma cells. They identified the BMP target ID3, which was strongly induced by BMP9 and whose loss protected cells from c-MYC downregulation and apoptosis. Mechanistically, ID3 regulate myeloma cell survival by interacting with basic helix-loop-helix transcription factors, particularly TCF3. Knockdown of TCF3, and to a lesser extent TCF12, reduced basal c-MYC expression and cell viability, effects that were further enhanced by BMP9 treatment.

 

Novel SLAMF1-derived peptide induces apoptosis in multiple myeloma cells by targeting IRF4 transcription factor for degradation

https://www.biorxiv.org/content/10.1101/2025.05.07.652607v1?rss=1

The authors describe a SLAMF1-derived peptide, P7N4, which exhibits potent anti-myeloma activity, reducing viability of IL-6-dependent and -independent myeloma cell lines, proteasome inhibitor-resistant cells, and primary MM cells while sparing healthy blood cells. P7N4 synergizes with melphalan and bortezomib ex vivo and in aggressive murine MM models. Mechanistically, it induces apoptosis by disrupting pro-survival pathways, lowering IRF4, MYC, and β-catenin levels, inhibiting Akt and ERK1/2 phosphorylation, and altering IRF4-associated gene expression, likely through direct interaction and degradation of IRF4. 
 

Longitudinal multi-omic profiling uncovers immune escape and predictors of response in multiple myeloma

https://www.biorxiv.org/content/10.1101/2025.05.27.656392v1?rss=1

From the authors: Longitudinal profiling of multiple myeloma and the immune microenvironment revealed dynamic immune-tumor interactions across the disease course. Dysfunctional CD8⁺ T cells limited memory formation post-transplant, while naïve B recovery associated with sustained treatment response. At progression, cancer-testis antigen expression associated with immunosuppression, revealing novel mechanisms of immune escape.
 

Bedaquiline Amplifies Proteasome Inhibitor Efficacy and Overcomes Resistance in Multiple Myeloma

https://www.biorxiv.org/content/10.1101/2025.06.29.661768v1?rss=1

From the authors: We identify the antimicrobial bedaquiline and its fumarate salt as potent enhancers of proteasome inhibitor efficacy in multiple myeloma and other B-cell malignancies. By inhibiting ATP synthase γ, bedaquiline amplifies chymotrypsin-like proteasome inhibition and overcomes drug resistance. This study reveals a mitochondria–proteasome vulnerability and proposes a clinically actionable strategy to restore sensitivity and reduce toxicity of proteasome-based therapies.
 

Methylation variability and LINE-1 activation in multiple myeloma

https://www.biorxiv.org/content/10.1101/2025.07.22.666173v1?rss=1

From the authors: Epigenome and transcriptional profiling of patient-derived multiple myeloma samples reveals heterogeneous loss of DNA methylation, reduction of KZFP expression and LINE-1 activation as a clinical indicator of progression.

 

Myeloid Chronic Malignancies

Unique epigenomic signatures identify biologically significant subtypes of MDS and predict response to azacitidine

https://www.biorxiv.org/content/10.1101/2025.04.23.650336v1?rss=1

From the authors: DNA methylation patterns define biologically meaningful MDS subtypes and uncover a new group lacking known mutations. A methylation-based signature at diagnosis predicts azacitidine response, supporting its use in guiding personalized MDS therapy.
 

Preclinical Efficacy of Tasquinimod in Myelodysplastic Neoplasms: Restoring Erythropoiesis and Mitigating Bone Loss

https://www.biorxiv.org/content/10.1101/2025.07.01.660147v1?rss=1

Here, the authors show that targeting inflammation with the S100A9 inhibitor tasquinimod (TASQ) improves hematopoietic and bone phenotypes in myelodysplastic neoplasms (MDS). TASQ blocked S100A9–TLR4 signaling in mesenchymal stromal cells, reducing inflammasome-associated pathways and restoring stromal support of hematopoiesis ex vivo. In an NHD13 MDS mouse model, TASQ treatment improved anemia and bone microarchitecture without affecting healthy controls. These findings indicate that inhibiting S100A9-driven inflammation can simultaneously enhance erythropoiesis and bone health in lower-risk MDS.

 

MDS-associated SF3B1 mutations promote aberrant fate choice of hematopoietic stem cell via mis-splicing of mediator kinase module component CDK8
https://www.biorxiv.org/content/10.1101/2025.08.14.670174v1?rss=1

Here, researchers identify CDK8 as a recurrent mis-spliced target of mutant SF3B1 in myelodysplastic syndromes with ring sideroblasts. Using primary human HSPCs, the authors show that CDK8 is a key regulator of progenitor homeostasis, with its depletion causing expansion of primitive HSPCs and a bias toward erythroid differentiation. Restoration of CDK8 rescues early erythroid defects in SF3B1-mutant cells, implicating CDK8 mis-splicing as a mechanistic driver of altered progenitor fate and dysplasia in SF3B1-mutant MDS.
 

Longitudinal single-cell RNA-sequencing reveals evolution of micro- and macro-states in chronic myeloid leukemia

https://www.biorxiv.org/content/10.1101/2025.05.14.653262v2

Single-cell RNA-seq of chronic myeloid leukemia (CML) reveals continuous transcriptional microstates, yet discrete disease-defining phenotypes emerge only at the pseudobulk (macrostate) level. Using state-transition theory, the study shows that robust phenotype transitions are driven by cell type–specific contributions. This framework explains why clinically relevant leukemia states are hidden at single-cell resolution and provides a generalizable strategy to link single-cell variability to macroscopic disease behavior.

 

Multimodal gene and targeted drug therapy for chronic myelogenous leukemia: Computational target analysis and therapeutic validation

https://www.biorxiv.org/content/10.1101/2025.05.26.656072v1?rss=1

BIM/MCL-1 chimeric nanoparticles (ChNPs), combining a BIM-expressing AAV core with MCL-1 siRNA, synergize with dasatinib to selectively kill BCR-ABL⁺ CML cells. In mouse CML models, this combination suppresses proliferation, prevents organ infiltration, and shows enhanced efficacy in acute-phase disease.

 

The transcriptional regulatory circuit as a driver and therapeutic target in CML blast crisis

https://www.biorxiv.org/content/10.1101/2025.11.02.686161v1?rss=1

From the authors: MEF2C, MYB, MEIS1, and ZEB2 form the CML blast-crisis transcriptional circuit, synergistically reprogramming chromatin and transcription. Mebendazole inhibits CML blast progression by impairing the circuit, offering a rapid translational strategy for this lethal phase.

 

Transcriptional readthrough precedes alternative splicing programs triggered in CML cells by imatinib

https://www.biorxiv.org/content/10.1101/2025.11.04.686193v1?rss=1

In this study, authors show that imatinib treatment rapidly increases the amount, length, and gene-specificity of readthrough within one hour, preceding gene expression and splicing changes. Notably, imatinib induces “readthrough chimeras”, where exons from upstream genes splice into downstream genes. These alterations persist in imatinib-resistant K562 cells and patient samples, indicating that early disruptions in transcription fidelity contribute to long-term gene expression changes and therapy resistance.
 

Deep single-cell immune and signaling profiles predict long term therapy response in chronic myeloid leukemia within hours

https://www.biorxiv.org/content/10.1101/2025.11.10.687542v1?rss=1

Here, researchers show that mass cytometry of peripheral blood from newly diagnosed chronic-phase CML patients can predict response to BCR::ABL1 tyrosine kinase inhibitors (TKIs). Dasatinib and nilotinib rapidly inhibited intracellular signaling within 1–3 hours, each producing distinct signaling signatures beyond BCR::ABL1 inhibition. By integrating immune and signaling profiles, the study could forecast patient responses over the first 12 months of therapy.

 

Targeting HMGA1-driven leukemic transformation in myeloproliferative neoplasms with pacritinib

https://www.biorxiv.org/content/10.1101/2025.06.01.657170v1?rss=1

From the authors: HMGA1 IHC staining serves as a readily implementable biomarker, outperforming existing marker for early prediction of MPN progression to sAML and identifying patients at high risk. Elevated HMGA1 expression correlates with resistance to first-generation JAK inhibitors and predicts poor overall survival in MPN-sAML patients, highlighting a critical unmet therapeutic need. The next-generation JAK2 inhibitor pacritinib effectively overcomes HMGA1-driven aggressive disease and therapy resistance, offering a rational, clinically available treatment strategy for HMGA1-high MPN-sAML.

 

Single JAK2-V617F hematopoietic stem cells can initiate MPN in transplantations into non-conditioned recipient mice

https://www.biorxiv.org/content/10.1101/2025.06.08.657469v1?rss=1

The authors show that JAK2-V617F mutant hematopoietic stem cells can efficiently engraft and initiate myeloproliferative neoplasms in non-conditioned mice, demonstrating strong intrinsic competitive fitness without irradiation or cytokine-driven niche disruption. Single mutant HSCs outcompete normal HSCs even at limiting dilutions. Immune surveillance distinguished human from mouse JAK2-V617F, with only the murine mutant escaping rejection in immunocompetent hosts. These findings could explain the frequent persistence of JAK2-V617F clones in clonal hematopoiesis.
 

JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones

https://www.biorxiv.org/content/10.1101/2025.09.23.678057v1?rss=1

Here, researchers show that progression from JAK2V617F-driven MPN to secondary AML can occur via parallel leukemic clones independent of the original JAK2 mutation. Using patient samples and in vivo models, they demonstrate that these pAML clones gain a selective advantage within the pro-inflammatory MPN environment. Inhibition of IL-12 and TNFα reduced this competitive growth.
 

The V617F mutation in JAK2 renders myeloid cells more sensitive to IL-6-mediated gp130 signaling

https://www.biorxiv.org/content/10.1101/2025.10.10.681590v1?rss=1

In this study, authors show that the JAK2V617F mutation enhances IL-6 signaling in myeloproliferative neoplasms by promoting gp130 receptor dimerization and surface expression. Molecular dynamics simulations indicated more stable JAK2VF pseudokinase dimers, potentially facilitating gp130 tetramer formation. Cell-based assays confirmed stronger STAT3 activation upon IL-6 stimulation in JAK2VF-expressing cells. These findings suggest that amplified IL-6/gp130 signaling contributes to chronic inflammation and MPN progression.

 

Effects of Calreticulin Mutations on HLA Class I Expression in Myeloproliferative Neoplasms

https://www.biorxiv.org/content/10.1101/2025.06.24.661416v1?rss=1

Here, the authors examined how myeloproliferative neoplasm–associated CALR mutations affect HLA class I assembly and surface expression. Using human cell lines and patient samples, they show that heterozygous CALR mutations largely preserve, or mildly increase, HLA class I expression, whereas complete loss of wild-type calreticulin leads to allele-dependent HLA class I deficiency that mutant CALR cannot fully rescue. Consistent with this, platelets and monocytes from CALR-mutant MPN patients generally display normal HLA class I levels, with higher expression observed in interferon-α–treated patients.

 

Effects of calreticulin deficiency and myeloproliferative neoplasm (MPN)-linked mutation on cellular calcium signaling

https://www.biorxiv.org/content/10.1101/2025.06.25.661618v1?rss=1

From the authors: Pathogenic CRTDel52 retains at least partial low-affinity calcium-binding capacity. Additionally, live-cell imaging and flow cytometry with ratiometric calcium probes indicate that ER and cytosolic calcium levels, as well as store-operated calcium entry (SOCE), are comparable in CRT-deficient cells rescued with either wild-type CRT or CRTDel52.

 

 

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

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