Preprint Watch: February

 

This month's curated selection of preprints cover some exciting new results on the impact of microenvironment on hematopoietic progenitors, molecular targets for potential new antileukemic agents and novel approaches to long-standing questions like self-renewal and stem cell activity!

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From the Simply Blood Community:

Dynamic activity of Erg promotes aging of the hematopoietic system 
https://www.biorxiv.org/content/10.1101/2025.01.23.634563v1?rss=1

From the authors: “The expression of ETS family transcription factor Erg is temporally regulated. Impaired upregulation of Erg during the hematopoietic maturation results in persistence of juvenile phenotypes.”

Path of differentiation defines human macrophage identity
https://www.biorxiv.org/content/10.1101/2025.01.24.634694v1

This work display how human fetal liver hematopoietic stem cells generate macrophages through two distinct pathways: a monocyte-dependent route that persists postnatally and a fetal-specific pathway that produces tissue-resident-like macrophages (TRMs) with self-renewal properties governed by the aryl hydrocarbon receptor (AHR). Furthermore, the authors inhibited the AHR, promoting TRM expansion and alleviating inflammation in atopic dermatitis models.


STEM AND PROGENITOR CELLS BIOLOGY

Holistic genetic barcoding reveals a lineage tree of tissue macrophage development
https://www.biorxiv.org/content/10.1101/2024.11.29.625985v1?rss=1

From the authors: “Holistic, time- and space-resolved barcoding in the embryo reveals a unified lineage tree for all tissue macrophages, generating local macrophage colonies persisting in adult organs.”

Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging
https://www.biorxiv.org/content/10.1101/2024.11.25.625252v1?rss=1

In this work, the authors highlighted how the downregulation of PF4 in the megakaryocytic niche plays an important role in HSC aging. Increased levels of PF4 restored HSC function, via the receptors LDLR and CXCR3

Clonal analysis of murine HSC self-renewal and differentiation in native hematopoiesis
https://www.biorxiv.org/content/10.1101/2024.11.22.624575v1?rss=1

Using the Sleeping Beauty transposon model in mice, the authors mapped over 70,000 clones, revealing that HSC self-renewal is closely linked to megakaryocytic differentiation, while more differentiated progenitors drive the bulk of clonal expansion for specific lineages.

Sepsis induces long-term reprogramming of human HSPCs and drives myeloid dysregulation in sepsis survivors
https://www.biorxiv.org/content/10.1101/2024.12.14.628447v1?rss=1

The authors looked at sepsis consequences on HSPCs, noting a long-term expansion of immature progenitors and metabolic dysregulation of their progeny. They also highlight the reprogramming effect of Type-I IFN signalling on macrophage differentiation, affecting their metabolic function and reducing cell proliferation.


PATHOLOGICAL HEMATOPOIESIS
Inhibition of RhoA-mediated secretory autophagy in megakaryocytes mitigates myelofibrosis in mice
https://www.biorxiv.org/content/10.1101/2024.12.04.626665v1?rss=1

From the authors: “ TGFβ1 is released from megakaryocytes via RhoA-mediated secretory autophagy, and targeting this process can alleviate fibrosis progression in a preclinical mouse model of myelofibrosis.”

Leukemia confers a durable imprint on healthy hematopoietic stem and progenitor cells
https://www.biorxiv.org/content/10.1101/2024.11.01.621509v1?rss=1

Here the authors looked at central trained immunity, an HSPC cell memory mechanism of inflammatory exposure. Using a leukemia model, they show that healthy HSPCs exposed to acute myeloid leukemia (AML) undergo lasting transcriptomic and epigenetic reprogramming, leading to heightened inflammatory and metabolic responses upon secondary challenge.

Exploring Mechanisms of Action in Combinatorial Therapies through Solubility Alterations: Advancing AML Treatment 
https://www.biorxiv.org/content/10.1101/2024.11.08.618644v3

To optimize drug synergy for developing AML therapeutic strategies, the authors propose a novel method called CoPISA. This proteomic approach identifies cooperative drug mechanisms, revealing a novel concept of "conjunctional inhibition" that enhances treatment strategies for AML and other complex diseases.

Bone marrow microenvironment signatures associate with patient survival after guadecitabine and atezolizumab therapy in HMA-resistant MDS
https://www.biorxiv.org/content/10.1101/2024.11.08.622670v1?rss=1

In this translational work, the authors looked at myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs). Patients face limited treatment options, which prompted a phase I/II clinical trial combining guadecitabine (HMA) and atezolizumab (immune checkpoint inhibitor). Single-cell profiling revealed that long-term survivors exhibited reduced immunosuppressive monocytes and enhanced effector lymphocytes, while short-term survivors retained inflammation and senescence-like features, suggesting bone marrow microenvironment characteristics could guide patient stratification for immunotherapy.

Spatial Transcriptomics Reveals Inflammation and Trans-differentiation States of Acute Myeloid Leukemia in Extramedullary and Medullary Tissues
https://www.biorxiv.org/content/10.1101/2024.11.11.622999v1?rss=1

Using a spatial transcriptomic approach, the authors mapped the medullary and extramedullary environments of acute myeloid leukemia (AML), revealing spatial co-localization of leukemic cells with monocytes and progenitors. Furthermore, they identified CXCL12-CXCR4 signaling linked to PI3K/AKT/mTOR activation in inflammatory niches and distinct AML differentiation states, highlighting the spatial hierarchy of AML.

Acute Myeloid Leukemia with deletion 5q is an epigenetically distinct subgroup defined by heterozygous loss of KDM3B
https://www.biorxiv.org/content/10.1101/2024.11.13.623380v1?rss=1

By analyzing DNA methylation profiles from 477 elderly AML patients using DNA methylome deconvolution, this study identified del(5q) AML as an epigenetically distinct subgroup with a hypermethylation signature. Further interrogation of the minimally deleted 5q region pinpointed KDM3B as a likely haploinsufficient target, suggesting that its loss disrupts H3K9me1/2 balance and contributes to leukemic progression.

Developmental Stage and Cellular Context Determine Oncogenic and Molecular Outcomes of Ezh2Y641F Mutation in Hematopoiesis
https://www.biorxiv.org/content/10.1101/2024.11.14.622807v2

Using a conditional allele with tissue-specific Cre drivers, this study examined the effects of the Ezh2Y641F mutation at different developmental stages in the hematopoietic system. While early or stem cell-specific expression caused hematopoietic defects and bone marrow failure, B cell-specific expression led to lymphoma, with transcriptomic analysis revealing altered IL2-Stat5 signaling, E2F target expression, and upregulated GBPs linked to Ezh2-mediated H3K27me3 regulation.


MOLECULAR HEMATOPOIESIS 

A distinct mechanism of RNA recognition by the transcription factor GATA1
https://www.biorxiv.org/content/10.1101/2024.12.02.626266v2

The authors demonstrated that GATA1, a key hematopoietic TF, binds RNA through an ARM-like domain that also contributes to DNA binding. Their findings reveal a competitive DNA/RNA binding mechanism, challenging the conventional view of RNA-binding domains and suggesting a potential role for RNA in regulating GATA1 function during hematopoiesis.

TCF3::HLF Orchestrates an Enhancer-Promoter Network with Activation of MEF2C to Promote Immature HSC gene Expression in Leukemia
https://www.biorxiv.org/content/10.1101/2024.11.26.625006v1?rss=1

From the authors: “Unraveling the 3D genomic interactions mediated by TCF3::HLF fusion protein in t(17;19) positive acute lymphoblastic leukemia.”

Small molecule targeting of FBXO21 mediated p85α ubiquitylation in acute myeloid leukemia
https://www.biorxiv.org/content/10.1101/2024.12.13.628427v1?rss=1

From the authors: “Our studies highlight the potential of the ubiquitin E3 ligase FBXO21 as an alternative therapeutic target for the PI3K signaling pathway, not only in AML but in cancers with aberrant PI3K signaling.”

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia
https://www.biorxiv.org/content/10.1101/2024.12.11.627663v1?rss=1

The authors investigate the roles of KAT6A, KAT6B, and KAT7 in MLL fusion oncoprotein (MLL-FP) leukemia, demonstrating that dual inhibition of KAT6 and KAT7 enhances therapeutic efficacy. Targeting KAT7 disrupts the MLL-FP transcriptional program, evicts MLL-FP from chromatin, and overcomes both primary and acquired resistance to Menin inhibitors.


TECH WATCH AND MODELING 

Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease
https://www.biorxiv.org/content/10.1101/2024.12.13.628398v1?rss=1

The authors developed a multiplex base editing strategy targeting the +58-kb and +55-kb BCL11A erythroid-specific enhancers to enhance fetal hemoglobin (HbF) production in sickle cell disease (SCD) without increasing mutagenic risk. Their approach efficiently reactivated HbF, surpassing CRISPR/Cas9 nuclease-based strategies, and demonstrated safety and long-term efficacy in hematopoietic stem/progenitor cells.

The comprehensive detection of hemoglobinopathy variants via long-read sequencing
https://www.biorxiv.org/content/10.1101/2024.12.03.626522v1?rss=1

The authors developed a long-read indexed PCR method using the CycloneSEQ nanopore sequencing platform to detect all variant types in hemoglobin genes, overcoming challenges posed by high GC content and homologous sequences. Validation in 507 clinical samples demonstrated high sensitivity and specificity, highlighting its potential for large-scale hemoglobinopathy screening and precise variant phasing for clinical interpretation.

Self-renewal without niche instruction, feedback or fine-tuning
https://www.biorxiv.org/content/10.1101/2024.12.20.629654v2

The authors propose a simple "dimerization cycle" mechanism by which stem cells achieve self-renewal autonomously, without requiring extrinsic feedback or fine-tuning. This mechanism leverages partitioning errors at cell division to establish asymmetric divisions and balance symmetric divisions, ensuring a stable stem cell population over time.

IFNα Inhibits JAK2V617F-Driven Neoplastic Vasculogenesis and Endothelial-to-Mesenchymal Transition in a 3D iPSC-Based Bone Marrow Niche Model
https://www.biorxiv.org/content/10.1101/2024.12.23.630035v1?rss=1

The authors developed a scalable 3D bone marrow niche model using patient-specific iPSCs to investigate the impact of JAK2V617F endothelial cells on neoplastic vasculogenesis in myeloproliferative neoplasms (MPN). Their findings reveal zygosity-dependent endothelial phenotypes and identify interferon-alpha (IFNα) as a potential inhibitor of endothelial-to-mesenchymal transition (EndMT).

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.