Novel therapeutics and targets in myelofibrosis

Waksal, Julian A.; Harrison, Claire; Mascarenhas, John

doi:10.1080/10428194.2021.2010068

Cited by 15 publications

(12 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to direct clinical application, objectively monitoring and quantitating fibrosis in BMTs is ideally suited for studies evaluating the effect of current therapies on disease progression in MPN. The outputs are also well suited for integration into future clinical trial designs evaluating novel therapeutic targets/drug candidates [ 44 , 45 ]. Without such approaches, incorporating marrow fibrosis assessment into robust clinical endpoints for the investigation of disease-modifying agents in myelofibrosis will remain challenging.…”

Section: Discussionmentioning

confidence: 99%

Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients

Ryou

Sirinukunwattana

Aberdeen³

et al. 2022

Leukemia

Self Cite

View full text Add to dashboard Cite

The grading of fibrosis in myeloproliferative neoplasms (MPN) is an important component of disease classification, prognostication and monitoring. However, current fibrosis grading systems are only semi-quantitative and fail to fully capture sample heterogeneity. To improve the quantitation of reticulin fibrosis, we developed a machine learning approach using bone marrow trephine (BMT) samples (n = 107) from patients diagnosed with MPN or a reactive marrow. The resulting Continuous Indexing of Fibrosis (CIF) enhances the detection and monitoring of fibrosis within BMTs, and aids MPN subtyping. When combined with megakaryocyte feature analysis, CIF discriminates between the frequently challenging differential diagnosis of essential thrombocythemia (ET) and pre-fibrotic myelofibrosis with high predictive accuracy [area under the curve = 0.94]. CIF also shows promise in the identification of MPN patients at risk of disease progression; analysis of samples from 35 patients diagnosed with ET and enrolled in the Primary Thrombocythemia-1 trial identified features predictive of post-ET myelofibrosis (area under the curve = 0.77). In addition to these clinical applications, automated analysis of fibrosis has clear potential to further refine disease classification boundaries and inform future studies of the micro-environmental factors driving disease initiation and progression in MPN and other stem cell disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients

Ryou

Sirinukunwattana

Aberdeen³

et al. 2022

Leukemia

Self Cite

View full text Add to dashboard Cite

show abstract

“…Fibrosis also occurred following the engraftment of organoids with HSPCs from patients with myelofibrosis, but not healthy donors. The ability to reliably model bone marrow fibrosis is an important advance, as the lack of adequate in vitro and in vivo models currently hampers the efficient preclinical validation of strategies aiming to reduce or prevent fibrosis, which is a huge unmet need for patients with myeloproliferative neoplasms and other blood cancers ( 45 ). As the organoids are highly reproducible and feasible to generate at scale in 96- or 384-well plate formats, this system presents an ideal platform for high-throughput target screens using pharmacologic or genetic modulation.…”

Section: Discussionmentioning

confidence: 99%

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

et al. 2022

View full text Add to dashboard Cite

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from iPSCs committed to mesenchymal, endothelial and hematopoietic lineages. These 3-dimensional structures capture key features of human bone marrow – stroma, lumen-forming sinusoids and myeloid cells including pro-platelet forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate discovery and prioritization of novel targets for bone marrow disorders and blood cancers.

show abstract

“…Fibrosis also occurred following engraftment of organoids with HSPCs from patients with myelofibrosis, but not healthy donors. The ability to reliably model bone marrow fibrosis is an important advance, as the lack of adequate in vitro and in vivo models currently hampers efficient pre-clinical validation of strategies aiming to reduce or prevent fibrosis, which is a huge unmet need for patients with myeloproliferative neoplasms and other blood cancers (56). As the organoids are highly reproductible and feasible to generate at scale in 96- or 384-well plate format, this system presents an ideal platform for high-throughput target screens using pharmacological or genetic modulation.…”

Section: Discussionmentioning

confidence: 99%

Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

Khan

Colombo

Reyat

et al. 2022

Preprint

View full text Add to dashboard Cite

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from iPSCs committed to mesenchymal, endothelial and hematopoietic lineages. These 3-dimensional structures capture key features of human bone marrow - stroma, lumen-forming sinusoidal vessels and myeloid cells including pro-platelet forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ ; stimulation and engraftment with myelofibrosis but not healthy donor-derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow-like milieu. This enabling technology is likely to accelerate discovery and prioritization of novel targets for bone marrow disorders and blood cancers.

show abstract

Novel therapeutics and targets in myelofibrosis

Cited by 15 publications

References 82 publications

Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients

Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

Contact Info

Product

Resources

About