Preprint Watch: January

The first monthly trawl for 2025 is plentiful: 9 preprints focusing on Acute Myeloid Leukemia, but also spatial fate mapping meets barcoding, how cell fate decisions occur in hematopoietic progenitors, and more! If there's a specific preprint you enjoyed and would like to see featured, please send it to us using this form.

STEM AND PROGENITOR CELLS BIOLOGY

Semaphorin 4A maintains functional diversity of the hematopoietic stem cell pool
https://www.biorxiv.org/content/10.1101/2024.11.12.622506v1?rss=1

The authors looked at Semaphorin 4A (Sema4A), a protein produced by neutrophils and signaling through Plexin D1, able to protect myeloid-biased hematopoietic stem cells (myHSCs) from inflammatory stress, preserving their epigenetic state and regenerative capacity. In the absence of Sema4A, myHSCs exhibit inflammatory hyper-responsiveness, leading to excessive expansion, myeloid bias, and impaired function with age.

Mitochondria Regulate the Cell Fate Decisions of Megakaryocyte-Erythroid Progenitors
https://www.biorxiv.org/content/10.1101/2024.11.17.623989v1?rss=1

The authors studied the role of mitochondria in hematopoietic progenitor lineage commitment, using a transgenic model of mitochondrial biology. By manipulating the mitochondrial function, the authors modified the erythroid differentiation in megakaryocyte-erythroid progenitors (MEPs), with mitochondria-rich MEPs favoring erythroid commitment and mitochondria-poor MEPs favoring megakaryocyte differentiation.

Comparative single-cell lineage bias in human and murine hematopoietic stem cells 
https://www.biorxiv.org/content/10.1101/2024.11.19.624262v1?rss=1

The study used mitochondrial single-cell ATAC-sequencing to track the differentiation potential of human HSCs, revealing that clonal lineages of human CD34+ cells differentiate normally without significant lineage bias. In vivo, transplantation of limited LT-HSCs into mice showed stochastic variation in myeloid and lymphoid cell engraftment, indicating that lineage commitment is influenced by the recipient niche rather than intrinsic biases of LT-HSCs.


LEUKEMIA AND PATHOLOGICAL HEMATOPOIESIS

Integrated scFv identification and CAR T cell generation for AML targeting in vivo
https://www.biorxiv.org/content/10.1101/2024.10.08.617189v1

In this study, the authors integrated scFv development using a phagemid library with CAR T cell generation. Screening for scFvs targeting CLL1 produced CAR T cells that specifically targeted Acute Myeloid Leukemia (AML) cells, reducing tumor burden and improving survival in vivo.

Germline and somatic genetic effects on gene expression and outcome in patients with Multiple Myeloma
https://www.biorxiv.org/content/10.1101/2024.10.09.617438v1

Multiple Myeloma (MM) is a hematological cancer with a poor prognosis and strong inherited component. This study revealed that non-coding germline variants influence the transcriptional landscape of MM, affecting transcription factors like IRF4 and contributing to patient survival.

Uncovering pre-sensitizing agents to FLT3 inhibitors in acute myeloid leukemia with ReSisTrace lineage tracing
https://www.biorxiv.org/content/10.1101/2024.10.22.619614v1?rss=1

Using single-cell lineage-tracing, this study identified pre-resistance transcriptional signatures and showed that targeting the gene GSPT1 or combining FLT3 inhibitors with different inhibitors can enhance sensitivity and reduce resistance in FLT3-ITD-positive AML. These findings offer new strategies for preventing treatment resistance in aggressive AML by targeting specific vulnerabilities in pre-resistant cells.

DNA methylation stochasticity is linked to transcriptional variability and identifies convergent epigenetic disruption across genetically-defined subtypes of AML
https://www.biorxiv.org/content/10.1101/2024.10.26.620422v1?rss=1

AML, with its low mutational burden and frequent epigenetic regulator mutations, shows unique methylation entropy patterns across subtypes. This study revealed that high-entropy subtypes, like those with CEBPA and IDH mutations, share a core program of epigenetic disruption affecting gene expression variability and leukemic signatures, suggesting a common epigenetic mechanism in AML.

DNMT3AR882H Is Not Required for Disease Maintenance in Primary Human AML, but Is Associated With Increased Leukemia Stem Cell Frequency
https://www.biorxiv.org/content/10.1101/2024.10.26.620318v1?rss=1

In AML, specific anomalies of the gene DNMT3A are crucial for disease initiation but largely dispensable for maintenance. The authors showed that correcting these mutations in AML cells minimally impacted their ability to engraft or altered their DNA methylation, highlighting that early oncogenic drivers may not be required for ongoing cancer survival, with potential implications for targeted therapies.

Single-Cell Atlas of AML Reveals Age-Related Gene Regulatory Networks in t(8;21) AML
https://www.biorxiv.org/content/10.1101/2024.10.29.620871v1?rss=1

In this preprint, the authors integrated multiple single-cell transcriptomic datasets, creating an atlas of 748,679 cells from 159 AML patients and 44 healthy donors, to explore the heterogeneity of acute myeloid leukemia. The analysis revealed age-associated gene regulatory network signatures, particularly in t(8;21) AML, and highlighted BCLAF1 as a promising prognostic indicator.

A novel in-vitro model of the bone marrow microenvironment in AML identifies CD44 and Focal Adhesion Kinase as therapeutic targets to reverse cell adhesion-mediated drug resistance
https://www.biorxiv.org/content/10.1101/2024.10.30.621120v1?rss=1

In this study, the authors developed an in-vitro co-culture model of the AML bone marrow microenvironment (BMME) to identify therapeutic agents that could disrupt AML cell adherence and reverse adhesion-mediated resistance. The combination of anti-CD44 treatment and the FAK inhibitor defactinib released AML cells from the protective BMME, with synergistic effects observed in reducing adhesion of CD34high AML cells.

Mutagenic impact and evolutionary influence of radiotherapy in hematologic malignancies
https://www.biorxiv.org/content/10.1101/2024.11.15.623836v1?rss=1

This study investigated the impact of ionizing radiotherapy (RT) on DNA damage and its role in the evolution of hematologic malignancies, particularly large B-cell lymphoma, multiple myeloma, and myeloid neoplasms. The researchers found that the ID8 mutational signature, associated with RT-induced DNA damage, was present in relapsed disease and could be used as a genomic barcode to track RT-resistant cells that may seed systemic relapse, highlighting the interplay between RT and chemotherapies.


MOLECULAR HEMATOPOIESIS

Cell fate determination is associated with changes in competing transcriptional units in the human GATA1 and GATA2 lineage-determining transcription factors 
https://www.biorxiv.org/content/10.1101/2024.11.08.622131v1?rss=1

This study investigated the role of promoter competition between GATA1 and GATA2 in regulating early cell fate decisions in hematopoietic progenitor cells. Promoter competition mechanisms, based on the activity of antisense promoters in both GATA2 and GATA1, control cell fate decisions, as described via single-cell RNA-sequencing of human CD34+ and in a 
differentiation assay on a leukemic cell line. 

Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse
https://www.biorxiv.org/content/10.1101/2024.11.09.622796v1?rss=1

This study identified significant alterations in IL-1 signaling in leukemia stem cells (LSCs) at diagnosis and relapse, with upregulation of IL-1 receptors (IL1R1 and IL1RAP) in both phases. The researchers developed UR241-2, a novel IRAK1/4 inhibitor, which effectively targets IL-1/IRAK1/4 signaling, selectively inhibiting LSC clonogenicity and engraftment while sparing normal hematopoietic stem cells.

Transcriptional Regulatory Logic Orchestrating Lymphoid and Myeloid Cell Fate Decisions
https://www.biorxiv.org/content/10.1101/2024.11.20.624578v1?rss=1

This study explored the gene regulatory circuitry controlling the development of B cells, T cells, innate lymphoid cells (ILCs), and dendritic cells (DCs), using Weighted Gene Co-expression Network Analysis (WGCNA) to identify lineage-specific transcription factors (TFs). The authors revealed conserved regulatory elements across immune cell types and provide insights into the regulatory mechanisms governing blood cell differentiation.

MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia
https://www.biorxiv.org/content/10.1101/2024.12.02.624182v2

(From the preprint) MOZ and HBO1 associate with NUP98 fusion oncoprotein condensates to drive leukemogenesis. Inhibition of their histone acetyltransferase activity is an effective therapeutic strategy in NUP98-rearranged leukemias, including those resistant to Menin inhibition. Moreover, combined MOZ/HBO1 and Menin inhibition is synergistic, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.


TECH WATCH AND MODELING

Polytope: High-resolution epitope barcoding for in vivo spatial fate-mapping
https://www.biorxiv.org/content/10.1101/2024.11.20.624484v1?rss=1

The study introduced "Polytope," an epitope barcoding system that generates up to 512 unique color codes for high-resolution, multiplexed imaging-based fate-mapping. Introducing Polytope in a mouse model, the authors successfully traced the fate of hundreds of clones across tissues from embryonic development to adulthood, providing a comprehensive tool for capturing complex clonal dynamics in situ.

A three-dimensional ex vivo model recapitulates in vivo features and unravels increased drug resistance in childhood acute lymphoblastic leukemia
https://www.biorxiv.org/content/10.1101/2024.12.13.628110v1?rss=1

This study developed a 3D bone marrow (BM) mimic with human mesenchymal stromal and endothelial cells to investigate the interaction between leukemic cells and their microenvironment. The model recapitulated key differences between B-cell and T-cell precursor acute lymphoblastic leukemia (ALL), revealing subtype-specific migration behaviors, drug resistance patterns, and cell cycle heterogeneity, while also offering a more accurate tool for detecting drug-resistant leukemic subpopulations compared to traditional 2D models.

Quantification of CAR T cell performance against acute myeloid leukemia using Bayesian inference
https://www.biorxiv.org/content/10.1101/2024.12.16.628628v1?rss=1

This study developed a mathematical model to predict the dynamics of CAR T cell expansion and tumor interactions, specifically targeting myeloid antigens on leukemic cells with varying TP53 genotypes. Using Bayesian inference and comparing candidate models, the best-performing model incorporated T cell elimination times and effector T cell self-interference, providing insights into long-term outcomes and optimizing CAR T cell dosing strategies for acute myeloid leukemia.

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.