Higher Degree by Research Application Portal

Myeloproliferative neoplasms (MPNs) are clonal haematopoietic disorders driven by constitutive JAK/STAT activation, leading to myeloid proliferation, chronic inflammation, and significant morbidity from arterial and venous thrombosis and potential to progress to myelofibrosis (MF) with marrow scarring and cytopenias. Current monitoring relies on peripheral blood counts and invasive marrow biopsies, which are limited for longitudinal assessment and early detection.

Platelets are a practical, minimally invasive biomarker source. As anucleate progeny of megakaryocytes (MKs), they inherit molecular signatures of marrow pathology and acquire functional changes that contribute to thrombosis. Our laboratory has identified transcriptomic, proteomic, and functional platelet changes in MPN which likely reflect changes in the parent megakaryocytes and are consistent with a prothrombotic yet exhausted phenotype. Platelet biomarkers therefore have potential to sensitively and non-invasively detect disease-specific signatures and monitor therapeutic response, including to emerging therapies.

Platelet–neutrophil aggregates (NPAs) are elevated in disease and drive thrombosis. Imaging flow cytometry platforms have the potential to classify NPAs with high accuracy. Immuno-Flow-FISH (IFF) adds a complementary approach to define the haemopoietic origin of molecular drivers of high-risk disease.

Hypothesis

Platelet molecular and functional signatures reflect changes in bone marrow progenitors and can be used to monitor MPN disease activity, including thrombotic risk, therapeutic response, and clonal origin.

Specific Aims

1. Characterise dynamic platelet transcriptomic changes during treatment with mutCALR bispecific antibodies and stem cell transplantation.

2. Identify biochemical and cytometric markers of platelets and platelet–neutrophil interactions associated with thrombosis using imaging flow cytometry and murine models.

3. Determine the progenitor origin of platelet and MK abnormalities using single-cell transcriptomic and immuno-flow-FISH analyses.

Significance and Innovation

Platelets offer a minimally invasive window into MPN biology, enabling early detection of thrombotic risk and disease transformation without serial marrow biopsies. This project will deliver biomarker platforms aligned with clinical trials, leveraging strong international collaborations.

Platelet Transcriptomics Studies (Aim 1)

WANMA Ideas - PlateletSeq: a novel blood test to assess cancer status in myeloproliferative neoplasms - CIA Guo (funded 2025-2026)

CCWA Project Grant - Platelet gene expression to monitor treatment of myelofibrosis, a bone marrow cancer - CIA Guo (funded 2023--2025)

CCWA Project Grant - Improving monitoring of patients with myelofibrosis after transplantation - CIA Guo (Funded 2025 - 2026)

CCWA Project Grant - Enabling Precision Monitoring of Response to Targeted Therapy in Myeloproliferative Neoplasms - CIA Linden (shortlisted for funding 2026)

NHMRC Ideas - Mapping the megakaryocyte transcriptome and marrow pathology in myelofibrosis - CIA Guo (applied for funding 2026 - 2029)

Thrombosis / NPA Studies (Aim 2)

UWA RCA Grant - Sticky Partners: Platelet–neutrophil crosstalk in myeloproliferative neoplasms and thrombosis - CIA Linden (aaplied for funding 2026)

Progenitor cell studies

RPH MRF Grant - A pathway to leukaemia prevention - CID Fuller (Funded 2025-2028)

NHMRC Ideas - Mapping the megakaryocyte transcriptome and marrow pathology in myelofibrosis - CIA Guo (applied for funding 2026 - 2029)

Matthew Linden

matthew.linden@uwa.edu.au

The Doctor of Philosophy (PhD) is a program of independent, supervised research that is assessed solely on the basis of a thesis, sometimes including a creative work component, that is examined externally. The work presented for a PhD must be a substantial and original contribution to scholarship, demonstrating mastery of the subject of interest as well as an advance in that field of knowledge. 

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