Recipient sex and donor leukemic cell characteristics determine leukemogenesis in patient-derived models

Haematologica, Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

In acute myeloid leukemia (AML), leukemogenesis depends on cell-intrinsic genetic aberrations and thus, studies AML require investigations in an vivo setting as provided by patient derived xenografts (PDX) models. Here we report that, next to leukemic cell characteristics, recipient sex highly influences the outgrowth of cells PDX models, with females being much better repopulated than males primary well secondary transplantation assays. Testosterone may be more important player since, strikingly, engraftment was seen castrated versus control male recipients, while ovariectomy did not significantly impair females. Shorter time-to-engraftment mouse survival were observed adverse molecular risk, respectively high FLT3-ITD ratio mutated cells. Adverse risk furthermore showed higher percentages phenotypic stem (LSCs), suggesting impaired differentiation capacity these subtypes. Overall, achieved successful repopulation 14/23 (61%) favorable, 18/30 (60%) intermediate 4/8 (50%) cases female Our data identify experimental confounder contribution hormones intriguing, underexplored research area.

Язык: Английский

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Deciphering the Complexities of Adult Human Steady State and Stress-Induced Hematopoiesis: Progress and Challenges

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 671 - 671

Опубликована: Янв. 14, 2025

Human hematopoietic stem cells (HSCs) have traditionally been viewed as self-renewing, multipotent with enormous potential in sustaining essential steady state blood and immune cell production throughout life. Indeed, around 86% (1011-1012) of new generated daily a healthy young human adult are origin. Therapeutically, HSCs contributed to over 1.5 million transplants (HCTs) globally, making this the most successful regenerative therapy date. We will commence review by briefly highlighting selected key achievements (from 1868 end 20th century) that accomplishment. Much our knowledge hematopoiesis is based on small animal models that, despite their importance, do not always recapitulate hematopoiesis. Given this, we critically progress challenges faced identifying tracing lineage differentiation trajectories, referring murine studies needed. Moving forward given dynamic can readily adjust variety stressors, then discuss recent research advances contributing understanding (i) which HSPCs maintain hematopoiesis, (ii) where these located, (iii) mechanisms come into play when homeostatic switches stress-induced or emergency

Язык: Английский

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Robust acute myeloid leukemia engraftment in humanized scaffolds using injectable biomaterials and intravenous xenotransplantation

Molecular Oncology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Patient‐derived xenografts (PDXs) can be improved by implantation of a humanized niche. Nevertheless, the overall complexity current protocols, as well use specific biomaterials and procedures, limits wider adoption this approach. Here, we identify essential minimum steps required to create scaffolds achieve successful acute myeloid leukemia (AML) engraftment. We compared seven biomaterials, which included both published custom‐designed materials. The highest level bone marrow niche was achieved with extracellular matrix gels custom collagen fiber, allowed for simple non‐surgical implantation. biomaterial selection did not influence following AML infiltration. Regarding xenotransplantation, standard intravenous administration produced most robust engraftment, even two out four otherwise non‐engrafting samples. In contrast, direct intra‐scaffold xenotransplantation offer any advantage. summary, demonstrate that combination an injectable scaffold creation plus route provide convenient approach produce PDX using

Язык: Английский

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Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 11, 2025

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions slow down progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail eradicate aberrant hematopoietic stem cells (HSCs), most of are mutated time diagnosis. Here, we sought elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias undetermined significance (CCUS), pre-malignant stage MDS. We used multi-omic single-cell approaches functional vitro studies show escape at initiation is mainly mediated mutant, dysfunctional natural killer (NK) impaired cytotoxic capability against cancer cells. Preclinical vivo demonstrated injecting NK from healthy donors efficiently depleted CCUS mutant while allowing normal regenerate hematopoiesis. Our findings suggest early intervention adoptive cell therapy prevent or delay development

Язык: Английский

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Patient‐derived xenografts: Practical considerations for preclinical drug testing

HemaSphere, Год журнала: 2025, Номер 9(4)

Опубликована: Апрель 1, 2025

Язык: Английский

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Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia

Leukemia, Год журнала: 2024, Номер 39(1), С. 8 - 24

Опубликована: Ноя. 11, 2024

The central role of the endothelial microenvironment in orchestrating bone marrow (BM) homeostasis and hematopoietic support has been confirmed at various developmental stages adult life. BM vasculature is crucial mediating communication between parenchyma circulating blood, displaying remarkable heterogeneity structure function. While vascular cell diversity other tissues long recognized, molecular basis this phenomenon just now emerging. Over past decade, single-cell approaches microscopic observations have expanded our understanding vasculature. solely characterized for their paracrine properties past, recent advances revolutionized perception function, revealing distinct anatomical locations associated with diverse states. identification phenotypic differences normal pathological conditions therefore deepened dynamics impact on hematopoiesis health disease. In review, we highlight key milestones within during development, adulthood aging. We also explore how leukemia affects can take knowledge forward to improve clinical practices. By synthesizing existing literature, aim address unresolved questions outline future research directions.

Язык: Английский

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Battle of the sexes: Understanding donor:recipient sex differences in transplantation biology

HemaSphere, Год журнала: 2024, Номер 8(9)

Опубликована: Сен. 1, 2024

Язык: Английский

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