Preprint Watch: November

The second edition of the Simply Blood Preprint Watch includes 14 preprints, covering clonal dynamics, AML biology and tumor-immune dynamics! We are also happy to showcase a preprint directly contributed by the community, so if you want to see your preprint featured as well, complete a brief submission form.

From the Simply Blood Community:

A Pax3 lineage gives rise to transient haematopoietic progenitors
https://www.biorxiv.org/content/10.1101/2024.06.26.600366v1 

This study describes a new source of transient haematopoietic progenitors in the mouse embryo belonging to a Pax3 lineage. These progenitors appear to be transient EMP-like cells that do not originate in the yolk sac and do not persist in adulthood. 

STEM AND PROGENITOR CELLS BIOLOGY

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy
https://www.biorxiv.org/content/10.1101/2024.09.09.612140v1

Somatic mutations in TET2, a common driver of clonal hematopoiesis, enhance the response to immune checkpoint blockade (ICB) in mice by promoting anti-tumor states in tumor-infiltrating leukocytes and improving T cell activation and memory. Clinically, melanoma patients with TET2 mutations show increased immune infiltration and are six times more likely to benefit from ICB, suggesting that TET2 inactivation could be a potential biomarker for personalized immunotherapy strategies.

Clonal dynamics and somatic evolution of haematopoiesis in mouse
https://www.biorxiv.org/content/10.1101/2024.09.17.613129v1

In this study, using single-cell-derived colonies from young and old mice, the authors identified 221,890 somatic mutations, revealing that mouse HSCs accrue approximately 45 mutations per year. Despite differences in lifespan and size, the study found that stem and multipotent progenitor pools independently self-renew over time, with aged mice displaying unique clonal expansion and selection that differ from the clonal diversity loss seen in human hematopoietic aging.

Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool
https://www.biorxiv.org/content/10.1101/2024.09.23.614531v1

The authors observed that embryonic hematopoietic stem and progenitor cells (HSPCs) maintain rapid proliferation and multipotency through Bnip3lb-mediated mitophagy, which regulates reactive oxygen species (ROS) during development. They also observed that mitophagy enhances HSPC function, and its induction improves the ex vivo capacity of hematopoietic progenitors derived from human induced pluripotent stem cells (hiPSCs).

LEUKEMIA AND PATHOLOGICAL HEMATOPOIESIS

Distinct Stromal Cell Populations Define the B-cell Acute Lymphoblastic Leukemia Microenvironment
https://www.biorxiv.org/content/10.1101/2024.09.10.612346v1

This study utilizes single-cell RNA sequencing to identify distinct mesenchymal stromal cell populations—early mesenchymal and adipogenic progenitors—as critical supportive niches for pediatric B-cell acute lymphoblastic leukemia (B-ALL). Notably, adipogenic progenitors support the survival of leukemic blasts ex vivo but are also enriched in relapse samples, highlighting their novel role in the B-ALL microenvironment.

SIRPα+ PD-L1+ bone marrow macrophages aid AML growth by modulating T cell function
https://www.biorxiv.org/content/10.1101/2024.09.15.613123v1

The authors investigate the role of non-malignant bone marrow macrophages in the progression of acute myeloid leukemia (AML), identifying a subpopulation of immunomodulatory macrophages (IMMs) that support AML growth by inhibiting T cells. IMMs enrichment in the bone marrow of patients who experience early relapse suggests that targeting these macrophages could improve treatment outcomes for AML patients.

DNA polymerase theta-mediated DNA repair is a functional dependency and therapeutic vulnerability in DNMT3A deficient leukemia cells
https://www.biorxiv.org/content/10.1101/2024.09.15.613155v1

Myeloid malignancies with somatic DNMT3A mutations are resistant to standard therapies and rely on DNA polymerase theta (Polθ) for survival, due to their accumulation of DNA double-strand breaks and replication fork collapse. The authors observed that the inhibition of Polθ enhances the effectiveness of conventional treatments, making it a therapeutic target for DNMT3Amut hematological malignancies.

PTPN11 Mutation Clonal Hierarchy in Acute Myeloid Leukemia
https://www.biorxiv.org/content/10.1101/2024.09.18.612239v1

PTPN11 mutations, traditionally seen as late events in AML, can also act as initiating mutations when paired with strong oncogenic drivers like NPM1 mutations. In this paper, authors show both in patient samples and a murine model that PTPN11 and NPM1 mutations were associated with diverse immune cell expansion, highlighting potential targets for immune-based therapies.

Hematological phenotypes in GATA2 deficiency syndrome arise from secondary injuries and maladaptation to proliferation
https://www.biorxiv.org/content/10.1101/2024.09.24.614663v1

The authors developed two individual mouse models of GATA2 haploinsufficiency, both mirroring human symptoms. They went on showing that leukemia arises from BMF driven by somatic aberrations, increased Myc target expression, and genomic instability, similar to what is observed in human patients with monosomy 7 and trisomy 8.

Pexidartinib plus FLT3-directed CAR-Macrophage for the treatment of FLT3-ITD-mutated acute myeloid leukemia in preclinical model
https://www.biorxiv.org/content/10.1101/2024.09.27.615313v1

Acute myeloid leukemia (AML) with FLT3-ITD mutations promotes M2-like leukemia-associated macrophages (M2-LAM) that impair phagocytosis and protect leukemia cells from inhibitor treatment. The authors describe how suppressing M2-LAM via dual inhibition reduces leukemic burden, while FLT3L-CAR-engineered macrophages enhanced phagocytic activity and prolonged survival in AML models. 

MOLECULAR HEMATOPOIESIS

Shared Genetic and Regulatory Mechanisms in Acute Myeloid Leukaemia and Blast Crisis Chronic Myeloid Leukaemia
https://www.biorxiv.org/content/10.1101/2024.10.26.620392v1?rss=1

AML and Blast Crisis (BC-) CML share clinical features like the accumulation of immature myeloid cells but differ in genetic profiles affecting disease progression and treatment response. This study identifies 29 common genes and highlights shared pathways, such as PI3K-AKT signaling, with potential therapeutic targets like TP53, RUNX1, and BCL2.

TECH WATCH AND MODELING

Real-time genomic characterization of pediatric acute leukemia using adaptive sampling
https://www.biorxiv.org/content/10.1101/2024.10.11.617690v1

Accurate genomic classification is essential for treating pediatric acute leukemia, but current methods are time-consuming and costly. This study shows that whole genome nanopore sequencing with adaptive sampling can rapidly and comprehensively classify chromosomal abnormalities and structural variants, providing a faster and more cost-effective alternative to traditional techniques.

Reducing oxidative stress improves ex vivo polymer-based human haematopoietic stem and progenitor cell culture and gene editing
https://www.biorxiv.org/content/10.1101/2024.09.17.613552v1

Building on previously published protocols, the authors describe the optimized use of polymer-based culture conditions to reduce oxidative stress, significantly improving human HSC growth up to 250-1400-fold. This protocol facilitates efficient gene editing and may support clinical-scale HSC expansion.

Predicting treatment-free remission outcomes in Chronic Myeloid Leukemia patients using an integrated model of tumor-immune dynamics
https://www.biorxiv.org/content/10.1101/2024.10.10.617526v1

Interactions between the tumor and immune system are crucial in determining treatment outcomes in Chronic Myeloid Leukemia (CML), influencing either treatment-free remission or disease recurrence. This study uses ecological modeling and time-course data on NK cells to predict CML treatment outcomes, suggesting that measuring immune cell populations can improve the accuracy of recurrence predictions after treatment cessation.

Blog post contributed by Alessandro Donada, PhD 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.