Biology subjects

Kurre, P.

Publications and source records attributed to Kurre, P..

5 recordsLinked to original sources

bioRxiv2024

Leukemia confers a durable imprint on healthy hematopoietic stem and progenitor cells

Recent models of infection and experimental inflammation reveal that hematopoietic stem and progenitor cells (HSPCs) can generate a memory of the exposure that heightens the response to subsequent stimulation, a process termed central trained immunity. Inflammation is also a constitutive feature of cancer, including hematologic malignancies. Here, we adapt a translationally relevant model of acute myeloid leukemia (AML) to determine if inflammation in the bone marrow (BM) niche durably reprograms resident healthy HSPCs. To simulate the onset of malignancy along with the associated inflammatory surge as well as the subsequent remission, we generated hematopoietic chimera with healthy HSPCs and HSPCs bearing a doxycycline-responsive oncogene (hMLL-AF9) expression cassette, a validated model of AML. Results show that the exposure to AML blasts in the BM leaves healthy HSPCs during experimental remission with broad transcriptomic, epigenetic changes and enhanced reliance on glycolysis. A heterologous secondary challenge of AML-experienced animals resulted in pronounced gene expression changes in inflammatory and metabolic pathways. These augmented responses coincided with altered chromatin accessibility in AML-experienced HSPCs. Motif analysis of the epigenome in AML trained HSPC points to the involvement of core hematopoietic transcription factors. Altogether, these observations provide first evidence for the durable inflammatory reprogramming of healthy HSPCs in the cancer microenvironment.

cancer biology↗

bioRxiv2024

Dynamic Tracking of Native Polyclonal Hematopoiesis in Adult Mice

Hematopoietic dysfunction has been associated with a reduction in the number of active precursors. However, precursor quantification at homeostasis and under diseased conditions is constrained by the scarcity of available methods. To address this issue, we optimized a method for quantifying a wide range of hematopoietic precursors. Assuming the random induction of a stable label in precursors following a binomial distribution, estimates depend on the inverse correlation between precursor numbers and the variance of precursor labeling among independent samples. Experimentally validated to cover the full dynamic range of hematopoietic precursors in mice (1 to 105), we utilized this approach to demonstrate that thousands of precursors, which emerge after modest expansion during fetal-to-adult transition, contribute to native and perturbed hematopoiesis. We further estimated the number of precursors in a mouse model of Fanconi Anemia, showcasing how repopulation deficits can be classified as autologous (cell proliferation) and non-autologous (lack of precursor). Our results support an accessible and reliable approach for precursor quantification, emphasizing the contemporary perspective that native hematopoiesis is highly polyclonal.

cell biology↗

bioRxiv2024

Effective Gene Therapy for Metachromatic Leukodystrophy Achieved with Minimal Lentiviral Genomic Integrations

Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease (LSD) characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplant (HSCT) with lentiviral (LV) based gene therapy has great potential to treat MLD. However, if enzyme production is inadequate, this could result in continued loss of motor function, implying a high vector copy number (VCN) requirement for optimal enzymatic output. This may place children at increased risk for genomic toxicity due to higher VCN. We increased the expression of ARSA cDNA at single integration by generating novel LVs, optimizing ARSA expression, and enhancing safety. In addition, our vectors achieved optimal transduction in mouse and human HSC with minimal multiplicity of infection (MOI). Our top-performing vector (EA1) showed at least 4X more ARSA activity than the currently EU-approved vector and a superior ability to secrete vesicle-associated ARSA, a critical modality to transfer functional enzymes from microglia to oligodendrocytes. Three-month-old Arsa-KO MLD mice transplanted with Arsa-KO BM cells transduced with 0.6 VCN of EA1 demonstrated behavior and CNS histology matching WT mice. Our novel vector boosts efficacy while improving safety as a robust approach for treating early symptomatic MLD patients.

molecular biology↗

bioRxiv2023

Inflammatory Recruitment of Healthy Hematopoietic Stem and Progenitor Cells in the Acute Myeloid Leukemia Niche

Inflammation in the bone marrow (BM) microenvironment is a constitutive component of leukemogenesis in acute myeloid leukemia (AML). Current evidence suggests that both leukemic blasts and stroma secrete proinflammatory factors that actively suppress the function of healthy hematopoietic stem and progenitor cells (HSPCs). HSPCs are also cellular components of the innate immune system, and we reasoned that they may actively propagate the inflammation in the leukemic niche. In two separate congenic models of AML we confirm by evaluation of the BM plasma secretome and HSPC-selective single-cell RNA sequencing (scRNA-Seq) that multipotent progenitors and long-lived stem cells adopt inflammatory gene expression programs, even at low BM leukemic burden. In particular, we observe interferon gamma (IFN-{gamma}) pathway activation, along with secretion of its chemokine target, CXCL10. We show that AML-derived nanometer-sized extracellular vesicles (EVAML) are sufficient to trigger this inflammatory HSPC response, both in vitro and in vivo. Altogether, our studies indicate that HSPCs are an unrecognized component of the inflammatory adaptation of the BM by leukemic cells. The pro-inflammatory conversion and long-lived presence of HSPC in the BM along with their regenerative re-expansion during remission may impact clonal selection and disease evolution.

cancer biology↗

bioRxiv2020

FANCD2 Alleviates Physiologic Replication Stress in Fetal Liver HSC

Bone marrow failure (BMF) in Fanconi Anemia (FA) results from exhaustion of hematopoietic stem cells (HSC), but the physiological role of FA proteins in HSC pool integrity remains unknown. Herein we demonstrate that FANCD2, a core component of the FA pathway, counters replication stress during developmental HSC expansion in the fetal liver (FL). Rapid rates of proliferation and FANCD2 deficient result in excess RPA-coated ssDNA, and provoke pChk1 activation and Cdkn1a(p21) nuclear localization in fetal Fancd2-/- HSC. Checkpoint mediated S-phase delays induced by Cdkn1a(p21) are rescued by Tgf-{beta} inhibition, but pChk1 activation is further aggravated. Our observations reveal the mechanism and physiological context by which FANCD2 safeguards HSC pool formation during development.

developmental biology↗